This invention is directed generally to proteinase (also known as xe2x80x9cproteasexe2x80x9d) inhibitors, and, more particularly, to sulfonyl aryl hydroxamates (also known as xe2x80x9csulfonyl aryl hydroxamic acidsxe2x80x9d) that, inter alia, inhibit matrix metalloproteinase (also known as xe2x80x9cmatrix metalloproteasexe2x80x9d or xe2x80x9cMMPxe2x80x9d) and/or aggrecanase activity. This invention also is directed to compositions of such inhibitors, intermediates for the syntheses of such inhibitors, methods for making such inhibitors, and methods for preventing or treating conditions associated with MMP activity, particularly pathological conditions.
Connective tissue is a required component of all mammals. It provides rigidity, differentiation, attachments, and, in some cases, elasticity. Connective tissue components include, for example, collagen, elastin, proteoglycans, fibronectin, and laminin. These biochemicals make up (or are components of) structures, such as skin, bone, teeth, tendon, cartilage, basement membrane, blood vessels, cornea, and vitreous humor.
Under normal conditions, connective tissue turnover and/or repair processes are in equilibrium with connective tissue production. Degradation of connective tissue is carried out by the action of proteinases released from resident tissue cells and/or invading inflammatory or tumor cells.
Matrix metalloproteinases, a family of zinc-dependent proteinases, make up a major class of enzymes involved in degrading connective tissue. Matrix metalloproteinases are divided into classes, with some members having several different names in common use. Examples are: MMP-1 (also known as collagenase 1, fibroblast collagenase, or EC 3.4.24.3); MMP-2 (also known as gelatinase A, 72 kDa gelatinase, basement membrane collagenase, or EC 3.4.24.24), MMP-3 (also known as stromelysin 1 or EC 3.4.24.17), proteoglycanase, MMP-7 (also known as matrilysin), MMP-8 (also known as collagenase II, neutrophil collagenase, or EC 3.4.24.34), MMP-9 (also known as gelatinase B, 92 kDa gelatinase, or EC 3.4.24.35), MMP-10 (also known as stromelysin 2 or EC 3.4.24.22), MMP-1 I (also known as stromelysin 3), MMP-12 (also known as metalloelastase, human macrophage elastase or HME), MMP-13 (also known as collagenase 111), and MMP-14 (also known as MT1-MMP or membrane MMP). See, generally, Woessner, J. F., xe2x80x9cThe Matrix Metalloprotease Familyxe2x80x9d in Matrix Metalloproteinases, pp. 1-14 (Edited by Parks, W. C. and Mecham, R. P., Academic Press, San Diego, Calif. 1998).
Excessive breakdown of connective tissue by MMPs is a feature of many pathological conditions. Inhibition of MMPs therefore provides a control mechanism for tissue decomposition to prevent and/or treat these pathological conditions. Such pathological conditions generally include, for example, tissue destruction, fibrotic diseases, pathological matrix weakening, defective injury repair, cardiovascular diseases, pulmonary diseases, kidney diseases, liver diseases, bone diseases, and diseases of the central nervous system. Specific examples of such conditions include, for example, rheumatoid arthritis, osteoarthritis, septic arthritis, multiple sclerosis, a decubitis ulcer, corneal ulceration, epidermal ulceration, gastric ulceration, tumor metastasis, tumor invasion, tumor angiogenesis, periodontal disease, liver cirrhosis, fibrotic lung disease, emphysema, otosclerosis, atherosclerosis, proteinuria, coronary thrombosis, dilated cardiomyopathy, congestive heart failure, aortic aneurysm, epidermolysis bullosa, bone disease, Alzheimer""s disease, and defective injury repair (e.g., weak repairs, adhesions such as post-surgical adhesions, and scarring).
Matrix metalloproteinases also are involved in the biosynthesis of tumor necrosis factors (TNFs). Tumor necrosis factors are implicated in many pathological conditions. TNF-xcex1, for example, is a cytokine that is presently thought to be produced initially as a 28 kD cell-associated molecule. It is released as an active, 17 kD form that can mediate a large number of deleterious effects in vitro and in vivo. TNF-xcex1 can cause and/or contribute to the effects of inflammation (e.g., rheumatoid arthritis), autoimmune disease, graft rejection, multiple sclerosis, fibrotic diseases, cancer, infectious diseases (e.g., malaria, mycobacterial infection, meningitis, etc.), fever, psoriasis, cardiovascular diseases (e.g., post-ischemic reperfusion injury and congestive heart failure), pulmonary diseases, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage, and acute phase responses like those seen with infections and sepsis and during shock (e.g., septic shock and hemodynamic shock). Chronic release of active TNF-xcex1 can cause cachexia and anorexia. TNF-xcex1 also can be lethal.
Inhibiting TNF (and related compounds) production and action is an important clinical disease treatment. Matrix metalloproteinase inhibition is one mechanism that can be used. MMP inhibitors (e.g., inhibitors of collagenase, stromelysin, and gelatinase), for example, have been reported to inhibit TNF-xcex1 release. See, e.g., Gearing et al. Nature, 376, 555-557 (1994). See also, McGeehan et al. See also, Nature 376, 558-561 (1994). MMP inhibitors also have been reported to inhibit TNF-xcex1 convertase, a metalloproteinase involved in forming active TNF-xcex1. See, e.g., WIPO Int""l Pub. No. WO 94/24140. See also, WIPO Int""l Pub. No. WO 94/02466. See also, WIPO Int""l Pub. No. WO 97/20824.
Matrix metalloproteinases also are involved in other biochemical processes in mammals. These include control of ovulation, post-partum uterine involution, possibly implantation, cleavage of APP (xcex2-amyloid precursor protein) to the ainyloid plaque, and inactivation of (xcex1I-protease inhibitor ((xcex1I-PI). Inhibiting MMPs therefore may be, for example, a mechanism to control of fertility. In addition, increasing and maintaining the levels of an endogenous or administered serine protease inhibitor (e.g., xcex1I-PI) supports the treatment and prevention of pathological conditions such as emphysema, pulmonary diseases, inflammatory diseases, and diseases of aging (e.g., loss of skin or organ stretch and resiliency).
Numerous metalloproteinase inhibitors are known. See, generally, Brown, P. D., xe2x80x9cSynthetic Inhibitors of Matrix Metalloproteinases,xe2x80x9d in Matrix Metalloproteinases, pp. 243-61 (Edited by Parks, W. C. and Mecham, R. P., Academic Press, San Diego, Calif. 1998).
Metalloproteinase inhibitors include, for example, natural biochemicals, such as tissue inhibitor of metalloproteinase (TIMP), (xcex12-macroglobulin, and their analogs and derivatives. These are high-molecular-weight protein molecules that form inactive complexes with metalloproteinases.
A number of smaller peptide-like compounds also have been reported to inhibit metalloproteinases. Mercaptoamide peptidyl derivatives, for example, have been reported to inhibit angiotensin converting enzyme (also known as ACE) in vitro and in vivo. ACE aids in the production of angiotensin II, a potent pressor substance in mammals. Inhibiting ACE leads to lowering of blood pressure.
A wide variety of thiol compounds also have been reported to inhibit MMPs. See, e.g., W095/12389. See also, W096/11209. See also, U.S. Pat. No. 4,595,700. See also, U.S. Pat. No. 6,013,649.
A wide variety of hydroxamate compounds also have been reported to inhibit MMPs. Such compounds reportedly include hydroxamates having a carbon backbone. See, e.g., WIPO Int""l Pub. No. WO 95/29892. See also, WIPO Int""l Pub. No. WO 97/24117. See also, WIPO Int""l Pub. No. WO 97/49679. See also, European Patent No. EP 0 780 386. Such compounds also reportedly include hydroxamates having peptidyl backbones or peptidomimetic backbones. See, e.g, WIPO Int""l Pub. No. WO 90/05719. See also, WIPO Int""l Pub. No. WO 93/20047. See also, WIPO Int""l Pub. No. WO 95/09841. See also, WIPO Int""l Pub. No. WO 96/06074. See also, Schwartz et al., Progr. Med. Chem., 29:271-334(1992). See also, Rasmussen et al., PharmacoL Ther., 75(1): 69-75 (1997). See also, Denis et al., Invest New Drugs, 15(3): 175-185 (1997). Sulfamato hydroxamates have additionally been reported to inhibit MMPs. See, WIPO Int""l Pub. No. WO 00/46221. And various aromatic sulfone hydroxamates have been reported to inhibit MMPs. See, WIPO Int""l Pub. No. WO 99/25687. See also, WIPO Int""l Pub. No. WO 00/50396. See also, WIPO Int""l Pub. No. WO 00/69821. See also, WIPO Int""l Pub. No. WO 98/38859 (disclosing, for example, sulfonyl aryl and heteroaryl hydroxamates). See also, WIPO Int""l Publ. No. WO 00/69819 (same).
It is often advantageous for an MMP inhibitor drug to target a certain MMP(s) over another MMP(s). For example, it is typically preferred to inhibit MMP-2, MMP-3, MMP-9, and/or MMP-13 (particularly MMP-13) when treating and/or preventing cancer, inhibiting of metastasis, and inhibiting angiogenesis. It also is typically preferred to inhibit MMP-13 when preventing and/or treating osteoarthritis. See, e.g., Mitchell et al., J Clin. Invest., 97:761-768 (1996). See also, Reboul et al., J Clin. Invest., 97:2011-2019 (1996). Normally, however, it is preferred to use a drug that has little or no inhibitory effect on MMP-1 and MMP-14. This preference stems from the fact that both MMP-1 and MMP-14 are involved in several homeostatic processes, and inhibition of MMP-1 and/or MMP-14 consequently tends to interfere with such processes.
Many known MMP inhibitors exhibit the same or similar inhibitory effects against each of the MMPs. For example, batimastat (a peptidomimetic hydroxamate) has been reported to exhibit IC50 values of from about 1 to about 20 nM against each of MMP-1, MMP-2, MMP-3, and MMP-9. Marimastat (another peptidomimetic hydroxamate) has been reported to be another broad-spectrum MMP inhibitor with an enzyme inhibitory spectrum similar to batimastat, except that Marimastat reportedly exhibited an IC50 value against MMP-3 of 230 nM. See Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997).
Meta analysis of data from Phase I/II studies using Marimastat in patients with advanced, rapidly progressive, treatment-refractory solid tumor cancers (colorectal, pancreatic, ovarian, and prostate) indicated a dose-related reduction in the rise of cancer-specific antigens used as surrogate markers for biological activity. Although Marimastat exhibited some measure of efficacy via these markers, toxic side effects reportedly were observed. The most common drug-related toxicity of Marimastat in those clinical trials was musculoskeletal pain and stiffniess, often commencing in the small joints in the hands, and then spreading to the arms and shoulder. A short dosing holiday of 1-3 weeks followed by dosage reduction reportedly permits treatment to continue. See Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997). It is thought that the lack of specificity of inhibitory effect among the MMPs may be the cause of that effect.
Another enzyme implicated in pathological conditions associated with excessive degradation of connective tissue is aggrecanase, particularly aggrecanase-1 (also known as ADAMTS-4). Specifically, articular cartilage contains large amounts of the proteoglycan aggrecan. Proteoglycan aggrecan provides mechanical properties that help articular cartilage in withstanding compressive deformation during joint articulation. The loss of aggrecan fragments and their release into synovial fluid caused by proteolytic cleavages is a central pathophysiological event in osteoarthritis and rheumatoid arthritis. It has been reported that two major cleavage sites exist in the proteolytically sensitive interglobular domains at the N-terminal region of the aggrecan core protein. One of those sites has been reported to be cleaved by several matrix metalloproteases. The other site, however, has been reported to be cleaved by aggrecanase-1. Thus, inhibiting excessive aggrecanase activity provides an additional and/or alternative prevention or treatment method for inflammatory conditions. See generally, Tang, B. L., xe2x80x9cADAMTS: A Novel Family of Extracellular Matrix Proteases,xe2x80x9d Int""l Journal of Biochemistry and Cell Biology, 33, pp. 33-44 (2001). Such diseases reportedly include, for example, osteoarthritis, rheumatoid arthritis, joint injury, reactive arthritis, acute pyrophosphate arthritis, and psoriatic arthritis. See, e.g., European Patent Application Publ. No. EP 1 081 137 A1.
In addition to inflammatory conditions, there also is evidence that inhibiting aggrecanase may be used for preventing or treating cancer. For example, excessive levels of aggrecanase-1 reportedly have been observed with a ghoma cell line. It also has been postulated that the enzymatic nature of aggrecanase and its similarities with the MMPs would support tumor invasion, metastasis, and angiogenesis. See Tang, Int""l Journal of Biochemistry and Cell Biology, 33, pp. 33-44 (2001).
Various hydroxamate compounds have been reported to inhibit aggrecanase-1. Such compounds include, for example, those described in European Patent Application Publ. No. EP 1 081 137 A1. Such compounds also include, for example, those described in WIPO PCT Int""l Publ. No. WO 00/09000. Such compounds further include, for example, those described in WIPO PCT Int""l Publ. No. WO 00/59874.
In view of the importance of hydroxamate MMP inhibitors in the prevention and treatment of several pathological conditions and the lack of enzyme specificity exhibited by 2 of the more potent MMP-inhibitor drugs that have been in clinical trials, there continues to be a need for hydroxamates having greater enzyme specificity (preferably toward MMP-2, MMP-9 and/or MMP-13, and even more particularly MMP-13), while exhibiting little or no inhibition of MMP-1 and/or MMP-14. There also continues to be a need for hydroxamate aggrecanase inhibitors that may be used to prevent or treat conditions associated with aggrecanase activity. The following disclosure describes hydroxamate compounds that tend to exhibit such desirable activities.
This invention is directed to compounds that inhibit MMP activity, particularly compounds that inhibit MMP-2, MMP-9, and/or MMP-13, while generally exhibiting relatively little or no inhibition against MMP-1 and MMP-14 activity. This invention also is directed to compounds that additionally or alternatively inhibit aggrecanase activity. This invention is further directed to a method for inhibiting MMP activity, particularly pathological MMP activity. Such a method is particularly suitable to be used with mammals, such as humans, other primates (e.g., monkeys, chimpanzees. etc.), companion animals (e.g., dogs, cats, horses. etc.), farm animals (e.g., goats, sheep, pigs, cattle, etc.), laboratory animals (e.g., mice, rats, etc.), and wild and zoo animals (e.g., wolves, bears, deer, etc.).
Briefly, therefore, the invention is directed, in part, to a sulfonyl aryl hydroxamic acid compound or salt thereof (particularly a pharmaceutically acceptable salt thereof).
In one embodiment, the sulfonyl aryl hydroxamic acid compound corresponds in structure to Formula VIIC:

In this embodiment:
W2 is a 6-member heterocyclic ring comprising the sulfonyl-bonded nitrogen.
xe2x80x94Axe2x80x94Rxe2x80x94Exe2x80x94Y is a substituent of W2 bonded at the 4-position of W2 relative to the sulfonyl-bonded nitrogen.
A is a bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94N(Rk)xe2x80x94, xe2x80x94C(O)xe2x80x94N(Rk)xe2x80x94, xe2x80x94N(Rk)xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(H)xe2x95x90C(H)xe2x80x94, xe2x80x94C Cxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94N(H)xe2x80x94N(H)xe2x80x94, xe2x80x94N(H)xe2x80x94C(O)xe2x80x94N(H)xe2x80x94, xe2x80x94C(S)xe2x80x94N(Rk)xe2x80x94, xe2x80x94N(Rk)xe2x80x94C(S)xe2x80x94, xe2x80x94C(H)2xe2x80x94, xe2x80x94Oxe2x80x94C(H)2xe2x80x94, xe2x80x94C(H)2xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94C(H)2xe2x80x94, or xe2x80x94C(H)2xe2x80x94Sxe2x80x94.
R is alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, or heterocycloalkylthioalkyl. Here, the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl optionally is substituted with 1 or 2 substituents selected from the group consisting of halogen, nitro, hydroxy, amino, alkyl, perfluoroalkyl, trifluoromethylalkyl, hydroxyalkyl, alkoxy, perfluoroalkoxy, perfluoroalkylthio, alkoxycarbonylalkyl, C1-C2-alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, alkanoylamino, and alkoxycarbonyl.
E is a bond, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Rgxe2x80x94, xe2x80x94Rgxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94N(Rk)xe2x80x94, xe2x80x94N(Rk)xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94Rgxe2x80x94, xe2x80x94Rgxe2x80x94S(O)2xe2x80x94, xe2x80x94N(Rk)xe2x80x94S(O)2xe2x80x94, or xe2x80x94S(O)2xe2x80x94N(Rk)xe2x80x94.
Y is absent or hydrogen, hydroxy, nitrile, nitro, alkyl, haloalkyl, aminoalkyl, alkoxy, perfluoroalkoxy, cycloalkyl, aryl, aralkyl, heteroaryl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, Ra-oxyalkyl, perfluoroalkylthio, alkenyl, heterocycloalkyl, or alkoxycarbonyl. Here, the aryl, heteroaryl, aralkyl, or heterocycloalkyl optionally is substituted with 1 or 2 substituents independently selected from the group consisting of halogen, nitro, nitrile, alkyl, haloalkyl, alkoxy, perfluoroalkoxy, and aminoalkanoyl, aralkyl, and aryl. The amino nitrogen of the aminoalkanoyl optionally is substituted with 1 or 2 substituents independently selected from alkyl and aralkyl.
R5 and R6 are independently selected from the group consisting of hydrogen, halogen, nitro, hydroxy, carboxy, cyano, xe2x80x94N(Rb)(Rc), alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, acylalkyl, cycloalkyl, thiol, alkylthio, arylthio, cycloalkylthio, hydroxyalkylthio, alkoxy, haloalkoxy, cycloalkoxy, alkoxyalkyl, alkoxyalkoxy, heterocyclooxy, N(Rb)(Rc)-alkyl, N(Rb)(Rc)-alkoxy, N(Rb)(Rc)-carbonyl, N(Rb)(Rc)-alkylthio, and N(Rb)(Rc)-sulfonyl. Alternatively, R5 and R6, together with the atoms to which they are bonded, form an aliphatic or aromatic carbocyclic or heterocyclic ring having 5 to 7 members.
Ra is hydrogen, alkyl, haloalkyl, N(Rb)(Rc)-alkyl, alkoxyalkyl, alkenyl, alkanoyl, haloalkanoyl, N(Rb)(Rc)-alkanoyl, aryl, arylalkyl, aroyl, arylalkylcarbonyl, or arylalkoxy.
Rb and Rc are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, carboxyalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, alkoxyalkyl, bisalkoxyalkyl, perfluoroalkoxyalkyl, alkanoyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, aryloxycarbonyl, arylsulfonyl, aralkanoyl, aroyl, aryliminocarbonyl, heterocyclo, heterocycloalkyl, heterocycloalkylcarbonyl, heteroaryl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, alkylsulfonyl, heteroarylsulfonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, aminoalkylcarbonyl, aminosulfonyl, and aminoalkylsulfonyl. Any amino nitrogen of Rb or Rc may be:
unsubstituted,
substituted with 1 or 2 Rd substituents, or
substituted with substituents such that the substituents, taken together with the amino nitrogen, form either:
a saturated or partially saturated heterocyclo optionally substituted with 1, 2, or 3 Rd substituents, or
a heteroaryl optionally substituted with 1, 2, or 3 Rf substituents.
Each Rd and Re is independently selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and arylalkoxycarbonyl.
Each Rf is independently selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, alkoxy, aryl, and xe2x80x94N(Rd)(Re).
Rg is hydrogen, halogen, hydroxy, cyano, amino, carboxy, alkyl, perfluoroalkyl, trifluoroalkyl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, aldehydo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkanoyl, alkylthio, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aroyl, heteroaroyl, aryloxy, heteroaryloxy, alkoxyaryl, alkoxyheteroaryl, alkylenedioxy, aryloxyalkyl, arylthio, alkoxycarbonyloxy, aryloxycarbonyl, arylalkoxycarbonyl, arylalkoxycarbonylamino, aryloxycarbonyloxy, xe2x80x94N(Rh)(Ri), N(Rh)(Ri)-carbonyloxy, N(Rh)(Ri)-carbonyl, N(Rh)(Ri)-alkanoyl, hydroxyaminocarbonyl, N(Rh)(Ri)-sulfonyl, N(Rh)(Ri)-carbonyl-N(Rh)xe2x80x94, trifluoromethylsulfonyl-N(Rh)xe2x80x94, heteroarylsulfonyl-N(Rh)xe2x80x94, arylsulfonyl-N(Rh)xe2x80x94, arylsulfonyl-N(Rh)-carbonyl, alkylsulfonyl-N(Rh)xe2x80x94, arylcarbonyl-N(Rh)-sulfonyl, or alkylsulfonyl-N(Rh)-carbonyl.
Each Rh is independently selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, unsubstituted aminoalkyl, substituted aminoalkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, arylalkyl, alkanoyl, haloalkanoyl, unsubstituted aminoalkanoyl, substituted aminoalkanoyl, aryl, arylalkoxycarbonyl, aroyl, heteroaryl, and heterocyclo. Here, each such group (including the substituents of any substituted amino alkyl or aminoalkanoyl) optionally is substituted by 1 or 2 Rj substituents
Ri is alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, unsubstituted aminoalkyl, substituted aminoalkyl, alkoxyalkyl,-alkoxycarbonyl, alkenyl, alkynyl, alkanoyl, haloalkanoyl, unsubstituted aminoalkanoyl, substituted aminoalkanoyl, aryl, arylalkyl, arylalkoxycarbonyl, aroyl, heteroaryl, or heterocyclo. Here, each such group optionally is substituted with 1 or 2 Rj substituents.
Each Rj is independently selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, unsubstituted aminoalkyl, substituted aminoalkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, alkanoyl, haloalkanoyl, unsubstituted aminoalkanoyl, substituted aminoalkanoyl, aryl, arylalkyl, arylalkoxycarbonyl, aroyl, heteroaryl, and heterocyclo. The substituents of the substituted aminoalkyl or substituted aminoalkanoyl are independently selected from the group consisting of alkyl, alkenyl, alkoxycarbonyl, aryl, arylalkyl, aryloxycarbonyl, heteroaryl, and heteroarylalkyl.
Rk is hydrogen, alkyl, alkenyl, alkoxycarbonyl, aryl, arylalkyl, aryloxycarbonyl, heteroaryl, heteroarylalkyl, N(Rc)(Rd)-carbonyl, N(Rc)(Rd)-sulfonyl, N(Rc)(Rd)-alkanoyl, or N(Rc)(Rd)-alkylsulfonyl.
In another embodiment, the sulfonyl aryl hydroxamic acid compound corresponds in structure to VIA-1:

In this embodiment:
W2 is a 6-member heterocyclic ring comprising the sulfonyl-bonded nitrogen.
R4 is a substituent of W2 bonded at the 4-position of W2 relative to the sulfonyl-bonded nitrogen. R4 has a chain length of from 3 to about 14 carbon atoms.
R5 and R6 are independently selected from the group consisting of hydrogen, halogen, nitro, hydroxy, carboxy, cyano, xe2x80x94N(Rb)(Rc), alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, acylalkyl, cycloalkyl, thiol, alkylthio, arylthio, cycloalkylthio, hydroxyalkylthio, alkoxy, haloalkoxy, cycloalkoxy, alkoxyalkyl, alkoxyalkoxy, heterocyclooxy, N(Rb)(Rc)-alkyl, N(Rb)(Rc)-alkoxy, N(Rb)(Rc)-carbonyl, N(Rb)(Rc)-alkylthio, and N(Rb)(Rc)-sulfonyl. Alternatively, R5 and R6, together with the atoms to which they are bonded, form a an aliphatic or aromatic carbocyclic or heterocyclic ring having 5 to 7 members.
R20 is xe2x80x94N(H)(OH).
Rb and Rc are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, carboxyalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, alkoxyalkyl, bisalkoxyalkyl, perfluoroalkoxyalkyl, alkanoyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, aryloxycarbonyl, arylsulfonyl, aralkanoyl, aroyl, aryliminocarbonyl, heterocyclo, heterocycloalkyl, heterocycloalkylcarbonyl, heteroaryl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, alkylsulfonyl, heteroarylsulfonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, aminoalkylcarbonyl, aminosulfonyl, and aminoalkylsulfonyl. Any amino nitrogen of Rb or Rc may be:
unsubstituted,
substituted with 1 or 2 Rd substituents, or
substituted with substituents such that the substituents, taken together with the amino nitrogen, form either:
a saturated or partially saturated heterocyclo optionally substituted with 1, 2, or 3 Rd substituents, or
a heteroaryl optionally substituted with 1, 2, or 3 Rf substituents.
Each Rd and Re is independently selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and arylalkoxycarbonyl.
Each Rf is independently selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, alkoxy, aryl, and xe2x80x94N(Rd)(Re).
This invention also is directed, in part, to a process for preventing or treating a condition associated with matrix metalloprotease activity in a host animal. The process comprises administering an above-described compound or pharmaceutically acceptable salt thereof to the host animal in an amount effective to prevent or treat the condition.
In one such embodiment, the condition comprises tissue destruction, a fibrotic disease, pathological matrix weakening, defective injury repair, a cardiovascular disease, a pulmonary disease, a bone disease, a central nervous system disease, or cancer. Specific examples of such conditions include osteoarthritis, rheumatoid arthritis, septic arthritis, tumor invasion, tumor metastasis, tumor angiogenesis, a gastric ulcer, a corneal ulcer, periodontal disease, multiple sclerosis, weak injury repair, an adhesion, scarring, congestive heart failure, coronary thrombosis, emphysema, proteinuria, and Alzheimer""s disease. Other specific examples include decubitis ulcer, fibrotic lung disease, otosclerosis, atherosclerosis, dilated cardiomyopathy, epidermolysis bullosa, and aortic aneurysm.
In another such embodiment, the condition comprises a liver condition (e.g., liver cirrhosis) or kidney condition.
This invention also is directed, in part, to a process for preventing or treating a condition associated with matrix metalloprotease activity in a host animal, wherein the process comprises administering an above-described compound or pharmaceutically acceptable salt thereof to the host animal in an amount effective to inhibit MMP-2, MMP-9, and/or MMP-13.
This invention also is directed, in part, to a process for preventing or treating a condition associated with TNF-xcex1 activity (including TNF-xcex1 convertase activity) in a host animal. In one embodiment, the prevention or treatment process comprises administering an above-described compound or pharmaceutically acceptable salt thereof to the host animal in an amount effective to prevent or treat a condition associated with TNF-xcex1 activity. Examples of such a condition include inflammation, a pulmonary disease, a cardiovascular disease, an autoimmune disease, graft rejection, a fibrotic disease, cancer, an infectious disease, fever, psoriasis, hemorrhage, coagulation, radiation damage, acute-phase responses of shock and sepsis, anorexia, and cachexia.
This invention additionally is directed, in part, to pharmaceutical compositions comprising the above-described compounds or pharmaceutically acceptable salts thereof, and the use of those compositions in the above-described prevention or treatment processes for a condition related to MMP, TNF-xcex1, and/or aggrecanase activity.
This invention further is directed, in part, to the use of the above-described compounds or pharmaceutically acceptable salts thereof for production of a medicament for use in the prevention or treatment of a condition related to MMP, TNF-xcex1, and/or aggrecanase activity.
Further benefits of Applicants"" invention will be apparent to one skilled in the art from reading this patent.
This detailed description of preferred embodiments is intended only to acquaint others skilled in the art with Applicants"" invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This detailed description and its specific examples, while indicating the preferred embodiments of this invention, are intended for purposes of illustration only. This invention, therefore, is not limited to the preferred embodiments described in this patent, and may be variously modified.
In accordance with this invention, it has been found that certain sulfonyl aryl or heteroaryl hydroxamates tend to be effective for inhibiting MMPs and/or aggrecanase. In the context of MMP inhibition, such hydroxamates tend to be particularly effective for inhibiting MMPs associated with excessive (or otherwise pathological) breakdown of connective tissue. More specifically, Applicants have found that these hydroxamates tend to be effective for inhibiting MMP-2 MMP-9, and/or MMP-13, which can be particularly destructive to tissue if present or generated in abnormally excessive quantities or concentrations. In addition, Applicants have discovered that these hydroxamates tend to be selective toward inhibiting MMP-2, MMP-9, and/or MMP-13 (as well as other MMPs associated with pathological condition conditions), and avoid excessive inhibition of other MMPs (particularly MMP-1 and MMP-14) essential to normal bodily function (e.g., tissue turnover and repair).
The present invention is directed, in part, to a sulfonyl aryl or heteroaryl hydroxamic acid compound, a salt of such a compound (such as a pharmaceutically acceptable salt, which can act as a matrix metalloprotease and/or aggrecanase inhibitor in a host animal), a precursor to such a compound, or a pro-drug form of such a compound.
The compounds used in this invention generally correspond in structure to Formula A:

Here, the ring structure W is a 5- or 6-member aromatic or heteroaromatic ring. Contemplated aromatic or heteroaromatic rings include, for example, 1,2-phenylene; 2,3-pyridinylenel; 3,4-pyridinylene; 4,5-pyridinylene; 2,3-pyrazinylene; 4,5-pyrimidinylene; and 5,6-pyrimidinylene. 1,2-Phenylene (a 1,2-disubstituted phenyl ring) is a particularly preferred W ring, and is therefore sometimes used illustratively herein as W.
Each of the variables y and z are zero or one such that the sum of x and y is either zero or 1.
Thus, when z is 1, the compound corresponds in structure to Formula A2:

Here, X is xe2x80x94CH2xe2x80x94or xe2x80x94N(R9)xe2x80x94, wherein R9 is hydrogen, aryl, alkyl, or arylalkyl. In an often preferred embodiment, X is xe2x80x94CH2xe2x80x94, i.e., the compound corresponds in structure to Formula A3:

When y is 1, the compound corresponds in structure to Formula A1:

In one such embodiment, R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, thiol, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, Ra-oxyalkyl, Ra-thioalkyl, xe2x80x94N(Rb)(Rc), N(Rb)(Rc)-alkyl, N(Rd)(Re)-alkanoyl-N(Rb)-alkyl, N(Rb)(Rc)-alkoxy, N(Rb)(Rc)-alkoxyalkyl, heterocyclo, heterocycloalkyl, heterocyclooxy, heterocyclothio, heteroaryl, heteroarylalkyl, heteroaryloxy, and heteroarylthio. In another embodiment, R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, C1-C4-alkyl, and amino.
Alternatively, R2 and R3, together with the carbon to which they are both bonded, form a 4- to 8-member (more preferably 5- to 6-member) carbocyclic or heterocyclic ring. Where such a ring is a heterocyclic ring, the heteroatom(s) in the ring is/are oxygen, sulfur, and/or nitrogen. Any such sulfur ring atom optionally may be substituted with 1 or 2 oxygens, and any such nitrogen ring atom may be substituted with C1-C4-hydrocarbyl, C3-C6-cyclohydrocarbyl, C1-C4-hydrocarbylcarbonyl, or C1-C4-hydrocarbylsulfonyl.
In an often particularly preferred embodiment, both y and z are zero so that the compound corresponds in structure to Formula C:

R5 and R6, together with the atoms to which R5 and R6 are both bonded, may form an aliphatic or aromatic carbocyclic or heterocyclic ring having from 5 to 7 members.
Alternatively, R5 and R6 are independently selected from the group consisting of hydrogen, halogen, nitro, hydroxy, carboxy, cyano, unsubstituted or substituted amino (i.e., xe2x80x94N(Rb)(Rc)), alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, acylalkyl, cycloalkyl, thiol, alkylthio, arylthio, cycloalkylthio, hydroxyalkylthio, alkoxy, haloalkoxy, cycloalkoxy, alkoxyalkyl, alkoxyalkoxy, heterocyclooxy, RbRc aminoalkyl (i.e., N(Rb)(Rc)-alkyl), RbRcaminoalkoxyl (i.e., N(Rb)(Rc)-alkoxy), RbRc aminocarbonyl (i.e., N(Rb)(Rc)-carbonyl), RbRcaminoalkylthio (i.e., N(Rb)(Rc)-alkylthio), and RbRcaminosulfonyl (i.e., N(Rb)(Rc)-sulfonyl).
In another embodiment, R5 and R6 are independently selected from the group consisting of hydrogen, halogen, nitro, hydroxy, cyano, alkyl, haloalkyl, hydroxyalkyl, acylalkyl, cycloalkyl, alkoxy, haloalkoxy, and RbRcaminoalkyl.
In still another embodiment, R5 and R6 are independently selected from the group consisting of hydrogen, hydrocarbyl (preferably C1-C4-hydrocarbyl), hydroxyhydrocarbyl, hydroxy, amino, dihydrocarbylamino, heterocyclo, heterocyclohydrocarbyl, heterocyclooxy, and heterocyclothio.
Rb and Rc are independently selected from the group consisting of hydrogen, alkyl, haloalkyl (preferably perfluoroalkyl or trifluoromethylalkyl), carboxyalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, alkoxyalkyl, bisalkoxyalkyl, perfluoroalkoxyalkyl, alkanoyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, aryloxycarbonyl, arylsulfonyl, aralkanoyl, aroyl, aryliminocarbonyl, heterocyclo, heterocycloalkyl, heterocycloalkylcarbonyl, heteroaryl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, alkylsulfonyl, heteroarylsulfonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, aminoalkylcarbonyl, aminosulfonyl, and aminoalkylsulfonyl. Any amino nitrogen of Rb or Rc may be:
unsubstituted,
substituted with 1 or 2 Rd substituents, or
substituted with substituents such that the substituents, taken together with the amino nitrogen, form either:
a saturated or partially saturated heterocyclo optionally substituted with 1, 2, or 3 Rd substituents, or
a heteroaryl optionally substituted with 1, 2, or 3 Rf substituents.
Each Rd and Re is independently selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and arylalkoxycarbonyl.
Each Rf is independently selected from the group consisting of halogen, cyano, nitro, hydroxy, alkyl, alkoxy, aryl, and xe2x80x94N(Rd)(Re).
In one embodiment, R20 is xe2x80x94Oxe2x80x94R21, wherein R21 is hydrogen, C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, or a pharmaceutically acceptable cation.
In another embodiment, R20 is xe2x80x94NR13xe2x80x94Oxe2x80x94R22, wherein R22 is a selectively removable protecting group; and R13 is hydrogen, C1-C6-alkyl, or benzyl.
In another embodiment, R20 is xe2x80x94NR23R24. R23 and R24 may independently be selected from the group consisting of hydrogen, C1-C6-alkyl, amino-C1-C6-alkyl, hydroxy-C1-C6-alkyl, aryl, and aryl-C1-C6-alkyl. Alternatively, R23 and R24, together with the nitrogen to which they are both bonded, may form a 5- to 8-member ring optionally containing an additional heteroatom that is oxygen, nitrogen, or sulfur.
In still another embodiment, R20 is xe2x80x94NR13xe2x80x94Oxe2x80x94R14, wherein R13 is hydrogen, C1-C6-alkyl, or benzyl; and R14 is hydrogen, a pharmaceutically acceptable cation, or xe2x80x94C(V)R15. Here, V is O or S; and R15 is C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, aryl-C1-C6-alkoxy, aryl-C1-C6-alkyl, heteroaryl, or amino-C1-C6-alkyl. As to the amino-C1-C6-alkyl nitrogen:
the amino-C1-C6-alkyl nitrogen may be unsubstituted;
the amino-C1-C6-alkyl nitrogen may be substituted with 1 or 2 substituents independently selected from the group consisting of C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryl-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl; or
the amino-C1-C6-alkyl nitrogen, together with the 2 substituents bonded thereto, may form a 5- to 8-member heterocyclo or heteroaryl ring.
In one such particularly preferred embodiment, R20 is N(H)(OH), and the compound corresponds in structure to Formula C4:

R1 is a substituent (i.e., radical, group, or moiety) that: (a) contains a 5- or 6-member cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl bonded directly to the depicted SO2 group; (b) has a length greater than about that of a hexyl group and less than about that of an eicosyl group; and (c) has a rotational width of from about that of a furanyl ring to about that of 2 phenyl rings. Initial studies indicate that so long as the R1 substituent falls within these criteria, the R1 substituent can be extremely varied.
Exemplary 5- or 6-member cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl groups that may bonded directly to the depicted SO2 group as part of R1 (and are themselves substituted as discussed herein) include phenyl; 2-, 3-, or 4-pyridyl; 2-naththyl; 2-pyrazinyl; 2- or 5-pyrimidinyl; 2- or 3-benzo(b)thienyl; 8-purinyl; 2 or 3-furyl; 2- or 3-pyrrolyl; 2-imidazolyl; cyclopentyl; cyclohexyl; 2-or 3-piperidinyl; piperazinyl, 2- or 3-morpholinyl; 2- or 3-tetrahydropyranyl; 2-imidazolidinyl; 2- or 3-pyrazolidinyl; and the like. Phenyl, piperidinyl, and piperazinyl are often particularly preferred, and are therefore sometimes used illustratively herein.
When examined along its longest chain of atoms, R1 has a total length equivalent to a length that is greater than that of a fully extended, saturated straight chain of 6 carbon atoms (i.e., a length greater than that of a hexyl group, or, in other words, a length of at least a heptyl chain in staggered conformation or longer), and a length that is less than that of a fully extended, saturated straight chain of about 20 carbons (i.e., a length less than that of an eicosyl group). Preferably, the length is from about 8 to about 18 carbon atoms (and often more preferably at least that of an octyl group and no greater than that of a palmityl group), even though many more atoms may be present in ring structures or substituents.
The R1 length is measured along the longest linear atom chain in the R1 substituent, following the skeletal atoms of a ring where necessary. Each atom in the chain (e.g., carbon, oxygen, or nitrogen) is presumed to be carbon for ease in calculation. Such lengths can be readily determined by using published bond angles, bond lengths, and atomic radii, as needed, to draw and measure a chain, or by building models using commercially available kits whose bond angles, lengths, and atomic radii are in accord with accepted, published values. R1 substituent lengths also can be determined somewhat less exactly by presuming, as is done here, that all atoms have bond lengths of saturated carbon, that unsaturated and aromatic bonds have the same lengths as saturated bonds, and that bond angles for unsaturated bonds are the same as those for saturated bonds, although the above-mentioned modes of measurement are preferred. To illustrate, a 4-phenyl or 4-pyridyl group has a length of a four carbon chain, as does a propoxy group. A biphenyl group, on the other hand, has a length of about an 8-carbon chain. Because a single-ring or fused-ring system cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl is generally not itself long enough to fulfill the length requirement for a preferred compound (particularly where R1 is xe2x80x94N(R7)(R8)), the R1 cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl bonded to directly to the sulfonyl is preferably itself substituted.
The length of R1 is believed to play a role in the overall activity of a contemplated inhibitor compound against MMP enzymes generally. Specifically, a compound having an R1 that is shorter in length than a heptyl group (e.g., 4-methoxyphenyl) typically exhibits moderate to poor inhibitory activity against all the MMP enzymes, whereas compounds containing an R1 substituent with a length of about an heptyl chain or longer (e.g., 4-phenoxyphenyl, which has a length of about a nine-carbon chain), typically exhibit good to excellent potencies against MMP-13 and/or MMP-2, and also selectivity against MMP-1. Exemplary data are provided in the Inhibition Tables hereinafter in which the activities of the two compounds mentioned above can be compared.
In addition to the preferred length, an R1 substituent also has a preferred rotational width. More specifically, an R1 substituent containing a 6-member ring bonded directly to the depicted SO2 group preferably has geometric dimensions such that if the R1 substituent were to be rotated about an axis drawn through the SO2-bonded 1-position and the 4-position of the SO2-bonded R1 ring, the 3-dimensional volume defined by the rotation would have a widest dimension in a direction transverse to the axis of rotation of from about that of a furanyl ring to about that of 2 phenyl rings. Likewise, an R1 substituent containing a 5-member ring bonded directly to the depicted SO2 group preferably has geometric dimensions such that if the R1 substituent were to be rotated about an axis drawn through the SO2-bonded 1-position and the center of the 3,4-bond of the SO2-bonded R1 ring, the 3-dimensional volume defined by the rotation would have a widest dimension in a direction transverse to the axis of rotation of from about that of a furanyl ring to about that of 2 phenyl rings. In this context, a fused ring system (e.g., naphthyl or purinyl) is considered to be a 6- or 5 member ring that is substituted at appropriate positions numbered from the SO2-linkage that is deemed to be at the 1-position. Thus, a 2-naphthyl substituent or an 8-purinyl substituent is an appropriately sized R1 radical as to the rotational width criterion. On the other hand, a 1-naphthyl group or a 7- or 9-purinyl group is too large upon rotation and therefore is excluded.
As a consequence of these preferred length and rotational width criteria, R1 substituents such as 4-(phenyl)phenyl [biphenyl], 4-(4xe2x80x2-methoxyphenyl)phenyl, 4-(phenoxy)phenyl, 4-(thiophenyl)phenyl [4-(phenylthio)phenyl], 4-(phenylazo)phenyl, 4-(phenylureido)phenyl, 4-(anilino)phenyl, 4-(nicotinamido)phenyl, 4-(isonicotinamido)phenyl, 4-(picolinamido)phenyl, and 4-(benzamido)phenyl, are among particularly preferred R1 substituents, with 4-(phenoxy)phenyl and 4-(thiophenyl)phenyl often being most preferred.
In some embodiments, R1 is xe2x80x94N(R7)(R8). In one such embodiment, R7 and R8 are independently selected from the group consisting of hydrogen, hydrocarbyl, aryl, substituted aryl, arylhydrocarbyl, and substituted arylhydrocarbyl. In a more preferred embodiment:
R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, Ra-oxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclo, each of which substituent optionally is independently substituted with an xe2x80x94Axe2x80x94Rxe2x80x94Exe2x80x94Y substituent (i.e., the substituent is unsubstituted or substituted with an xe2x80x94Axe2x80x94Rxe2x80x94Exe2x80x94Y substituent); or
R7 and R8, together with the nitrogen to which they are both attached, form a substituent xe2x80x94Gxe2x80x94Axe2x80x94Rxe2x80x94Exe2x80x94Y, wherein G is an N-heterocyclo group substituted with an xe2x80x94Axe2x80x94Rxe2x80x94Exe2x80x94Y substituent.
With respect to the xe2x80x94Axe2x80x94Rxe2x80x94Exe2x80x94Y substituent, A is a bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94N(Rk)xe2x80x94, xe2x80x94C(O)xe2x80x94N(Rk)xe2x80x94, xe2x80x94N(Rk)xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(H)xe2x95x90C(H)xe2x80x94, xe2x80x94C Cxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94N(H)xe2x80x94N(H)xe2x80x94, xe2x80x94N(H)xe2x80x94C(O)xe2x80x94N(H)xe2x80x94, xe2x80x94C(S)xe2x80x94N(Rk)xe2x80x94, xe2x80x94N(Rk)xe2x80x94C(S)xe2x80x94, xe2x80x94C(H)2xe2x80x94, xe2x80x94Oxe2x80x94C(H)2xe2x80x94, xe2x80x94Oxe2x80x94C(H)2xe2x80x94, xe2x80x94C(H)2xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94C(H)2xe2x80x94, or xe2x80x94C(H)2xe2x80x94Sxe2x80x94.
R is alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, or heterocycloalkylthioalkyl. The aryl, heteroaryl, cycloalkyl, or heterocycloalkyl optionally is substituted with 1 or 2 substituents selected from the group consisting of halogen (or xe2x80x9chaloxe2x80x9d; F, Cl, Br, I), nitro, hydroxy, amino, alkyl, perfluoroalkyl, trifluoromethylalkyl, hydroxyalkyl, alkoxy, perfluoroalkoxy, perfluoroalkylthio, alkoxycarbonylalkyl, C1-C2-alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, alkanoylamino, and alkoxycarbonyl.
E is a bond, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Rgxe2x80x94, xe2x80x94Rgxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94N(Rk)xe2x80x94, xe2x80x94N(Rk)xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94Rgxe2x80x94, xe2x80x94Rgxe2x80x94S(O)2xe2x80x94, xe2x80x94N(Rk)xe2x80x94S(O)2xe2x80x94, or xe2x80x94S(O)2xe2x80x94N(Rk)xe2x80x94.
Y is absent or hydrogen, hydroxy, nitrile, nitro, alkyl, haloalkyl (preferably trifluoromethylalkyl or trifluoromethyl), aminoalkyl, alkoxy, perfluoroalkoxy, cycloalkyl, aryl, aralkyl, heteroaryl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, Ra-oxyalkyl, perfluoroalkylthio, alkenyl, heterocycloalkyl, or alkoxycarbonyl. Here, the aryl, heteroaryl, aralkyl, or heterocycloalkyl optionally is substituted with 1 or 2 substituents independently selected from the group consisting of halogen, nitro, nitrile, alkyl, haloalkyl (preferably perfluoroalkyl), alkoxy, perfluoroalkoxy, and aminoalkanoyl, aralkyl, and aryl. The amino nitrogen optionally is substituted with 1 or 2 substituents independently selected from alkyl and aralkyl.
Ra is hydrogen, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, RbRcaminoalkanoyl, haloalkanoyl, RbRcaminoalkyl, alkoxyalkyl, haloalkyl, or arylalkoxy.
Rg is hydrogen, halogen, hydroxy, cyano, amino, carboxy, alkyl, perfluoroalkyl, trifluoroalkyl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, aldehydo (CHO, formyl), alkoxy, alkoxyalkyl, alkoxycarbonyl, alkanoyl, alkylthio, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aroyl, heteroaroyl, aryloxy, heteroaryloxy, alkoxyaryl, alkoxyheteroaryl, alkylenedioxy, aryloxyalkyl, arylthio, alkoxycarbonyloxy, aryloxycarbonyl, arylalkoxycarbonyl, arylalkoxycarbonylamino, aryloxycarbonyloxy, xe2x80x94N(Rh)(Ri), N(Rh)(Ri)-carbonyloxy, N(Rh)(Ri)-carbonyl, N(Rh)(Ri)-alkanoyl, hydroxyaminocarbonyl, N(Rh)(Ri)-sulfonyl, N(Rh)(Ri)-carbonyl-N(Rh)xe2x80x94, trifluoromethylsulfonyl-N(Rh)xe2x80x94, heteroarylsulfonyl-N(Rh)xe2x80x94. arylsulfonyl-N(Rh)xe2x80x94, arylsulfonyl-N(Rh)-carbonyl, alkylsulfonyl-N(Rh)xe2x80x94, arylcarbonyl-N(Rh)-sulfonyl, or alkylsulfonyl-N(Rh)-carbonyl.
Each Rh is independently selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, unsubstituted aminoalkyl, substituted aminoalkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, arylalkyl, alkanoyl, haloalkanoyl, unsubstituted aminoalkanoyl, substituted aminoalkanoyl, aryl, arylalkoxycarbonyl, aroyl, heteroaryl, and heterocyclo. Each such group (including the substituents of any substituted amino alkyl or aminoalkanoyl) optionally is substituted by 1 or 2 Rj substituents.
Ri is alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, unsubstituted aminoalkyl, substituted aminoalkyl, alkoxyalkyl, alkoxycarbonyl, alkenyl, alkynyl, alkanoyl, haloalkanoyl, unsubstituted aminoalkanoyl, substituted aminoalkanoyl, aryl, arylalkyl, arylalkoxycarbonyl, aroyl, heteroaryl, or heterocyclo. Each such group optionally is substituted with 1 or 2 Rj substituents.
Each Rj is independently selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, unsubstituted aminoalkyl, substituted aminoalkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, alkanoyl, haloalkanoyl, unsubstituted aminoalkanoyl, substituted aminoalkanoyl, aryl, arylalkyl, arylalkoxycarbonyl, aroyl, heteroaryl, and heterocyclo. The substituents of the substituted aminoalkyl or substituted aminoalkanoyl are independently selected from the group consisting of alkyl, alkenyl, alkoxycarbonyl, aryl, arylalkyl, aryloxycarbonyl, heteroaryl, and heteroarylalkyl.
Rk is hydrogen, alkyl, alkenyl, alkoxycarbonyl, aryl, arylalkyl, aryloxycarbonyl, heteroaryl, heteroarylalkyl, N(Rc)(Rd)-carbonyl, N(Rc)(Rd) sulfonyl, N(Rc)(Rd)-alkanoyl, or N(Rc)(Rd)-alkylsulfonyl.
Some embodiments of this invention contemplate a compound that corresponds in structure to Formula VI-1 below:

Here, R5, R6, R7, R8, and R20 are as defined above. Each of A, B, C, and D is carbon, nitrogen, sulfur, or oxygen, and is present or absent so that the depicted ring has 5- or 6-members. A hydroxamate compound of Formula VI-1 tends to be a selective inhibitor of MMP-2 over both of MMP-1 and MMP-13. That is, a hydroxamate compound of Formula VI-1 tends to exhibit greater activity in inhibiting MMP-2 than in inhibiting either MMP-1 and usually also MMP-13. In one such embodiment, the compound corresponds in structure to Formula VIB:

Again, R20, R5, R6, R7, and R8 are as defined above.
In a particularly preferred embodiment, the compound corresponds in structure to either Formula VIA or Formula VIA-1:

Here, R20, R5, and R6 are as defined above.
Ring structure W2, including the depicted nitrogen atom (i.e., the sulfonyl-bonded nitrogen), is a heterocyclic ring that contains 5 or 6 ring members (with 6 ring members often being more preferred). In a particularly preferred embodiment, the ring structure W2 is N-piperidinyl. In a another particularly preferred embodiment, the ring structure W2 is N-piperazinyl.
R4 is a substituent that preferably is bonded at the 4-position of W2 (relative to the depicted nitrogen atom) when W2 is a 6-member ring, and at the 3-or 4-position of W2 (relative to the depicted nitrogen) when W2 is a 5-member ring. R4 preferably is a substituent that has a chain length of from 3 to about 14 carbon atoms. More specifically, R4 preferably is an optionally-substituted (i. e., unsubstituted or substituted) single-ring cyclohydrocarbyl, single-ring heterocyclo, single-ring aryl, single-ring heteroaryl, or other substituent having a chain length of from 3 to about 14 carbon atoms, such as hydrocarbyl (e.g., C3-C14 hydrocarbyl), hydrocarbyloxy (e.g., C2-C14-hydrocarbyloxy), phenyl, phenoxy (xe2x80x94Oxe2x80x94C6H5), thiophenoxy (phenylsulfanyl; xe2x80x94Sxe2x80x94C6H5), anilino (xe2x80x94NHxe2x80x94C6H5), phenylazo (xe2x80x94N2-C6H5), phenylureido (aniline carbonylamino; xe2x80x94NHC(O)NHxe2x80x94C6H5), benzamido (xe2x80x94NHC(O)xe2x80x94C6H5), nicotinamido (-3xe2x80x94NHC(O)C5H4N), isonicotinamido (-4xe2x80x94NHC(O)C5H4N), or picolinamido (-2xe2x80x94NHC(O)C5H4N). Additional contemplated R4 substituents include optionally-substituted heterocyclo, heterocyclohydrocarbyl, arylhydrocarbyl, arylheterocyclohydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, or heteroarylthio. Where these groups are substituted, they preferably are substituted with one or more substituents selected from the group consisting of halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethyl hydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonyl hydrocarbyl, heterocyclooxy, hydroxycarbonyl hydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroaryl hydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxy hydrocarbyloxy, hydrocarbylthio, hydrocarbyloxy hydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxy carbonylhydrocarbyl, hydrocarbylhydroxycarbonyl hydrocarbylthio, hydrocarbyloxycarbonyl hydrocarbyloxy, hydrocarbyloxycarbonyl hydrocarbylthio, amino, hydrocarbylcarbonylamino., arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroaryl carbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbyl sulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino, and N-mono substituted or N,N-disubstituted aminohydrocarbyl. The substituent(s) on the mono or di-substituted aminohydrocarbyl nitrogen are selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl. Alternatively, in the case of a disubstituted aminohydrocarbyl, the substituents, together with the aminohydrocarbyl nitrogen, form a 5- to 8-member heterocyclic or heteroaryl ring group.
Where R4 is a substituted 6-member ring, the 6-member ring preferably is substituted at the meta- or para-position (or both) with a single atom or a substituent containing a longest chain of up to 10 atoms, excluding hydrogen. For example, R4 may be a phenyl, phenoxy, thiophenoxy, phenylazo, phenylureido, anilino, nicotinamido, isonicotinamido, picolinamido, or benzamido that optionally is itself substituted at its own meta or para-position (or both) with a substituent(s) that is selected from the group consisting of halogen, halohydrocarbyl, halo-C1-C9 hydrocarbyloxy, perfluoro-C1-C9 hydrocarbyl, C1-C9 hydrocarbyloxy (xe2x80x94Oxe2x80x94C1-C9-hydrocarbyl), C1-C10-hydrocarbyl, di-C1-C9-hydrocarbylamino (xe2x80x94N(C1-C9 hydrocarbyl)(C1-C9 hydrocarbyl)), carboxy-C1-C8-hydrocarbyl, C1-C4-hydrocarbyloxy carbonyl-C1-C4-hydrocarbyl (C1-C4-hydrocarbyl-Oxe2x80x94(CO)xe2x80x94C1-C4-hydrocarbyl), C1-C4-hydrocarbyloxycarbonyl-C1-C4-hydrocarbyl (C1-C4-hydrocarbyl-Oxe2x80x94(CO)xe2x80x94C1-C4 hydrocarbyl), and C1-C8-hydrocarbyl carboxamido (xe2x80x94NH(CO)xe2x80x94C1-C8-hydrocarbyl); or is substituted at the meta- and para-positions by 2 methyl groups or by a C1-C2-alkylenedioxy group (e.g., methylenedioxy).
In still a further embodiment of this invention, R1 is an SO2-linked 5- or 6-member cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl that is itself substituted with an R4 substituent. When the SO2-linked cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl is a 6-member ring, it is preferably substituted by the R4 substituent at its own 4-position. When the SO2-linked cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl is a 5-member ring, it is preferably substituted by the R4 substituent at its own 3 or 4-position.
Inasmuch as a contemplated SO2-linked cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl of R1 is itself preferably substituted with a 6-member aromatic ring, two nomenclature systems are used together herein for ease in understanding substituent positions. The first system uses position numbers for the ring directly bonded to the SO2-group, whereas the second system uses ortho, meta, or para for the position of one or more substituents of a 6-member ring bonded to an SO2-linked cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl radical. When an R4 substituent is other than a 6-member ring, substituent positions are numbered from the position of linkage to the aromatic or heteroaromatic ring. Formal chemical nomenclature is used in naming particular compounds. Thus, the I-position of an above-discussed SO2-linked cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl is the position at which the SO2 group is bonded to the ring. The 4- and 3-positions of the rings discussed here are numbered from the sites of substituent bonding from the SO2-linkage as compared to formalized ring numbering positions used in heteroaryl nomenclature.
A compound of Formula A (and more preferably Formula C) embraces a useful precursor compound, a pro-drug form of a hydroxamate, and the hydroxamate itself, as well as amide compounds that can be used as intermediates and also as MMP inhibitor compounds. Thus, for example, where R20 is xe2x80x94Oxe2x80x94R21 (in which R21 is selected from the group consisting of a hydrogen, C1-C6-alkyl, aryl, aryl-C1-C6-alkyl group, and a pharmaceutically acceptable cation), a precursor carboxylic acid or ester is defined that can be readily transformed into a hydroxamic acid, as is illustrated in several Examples hereinafter. It should be recognized that such a precursor compound also can have activity as an inhibitor of MMP enzymes and/or aggrecanase.
Another useful precursor compound is defined when R20 is xe2x80x94NR13xe2x80x94Oxe2x80x94R22, wherein R22 is a selectively removable protecting group, and R13 is a hydrogen or benzyl (preferably hydrogen). Examples of selectively removable protecting groups include 2-tetrahydropyranyl (THP), benzyl, p-methoxybenzyloxycarbonyl (MOZ), benzyloxycarbonyl (BOC), C1-C6-alkoxycarbonyl, C1-C6-alkoxyxe2x80x94CH2xe2x80x94, C1-C6-alkoxy-C1-C6-alkoxyxe2x80x94CH2xe2x80x94, trisubstituted silyl, o-nitrophenyl, peptide synthesis resin, and the like.
A contemplated trisubstituted silyl group is a silyl group substituted with C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, or a mixture thereof. Examples include trimethylsilyl, triethylsilyl, butyldiphenylsilyl, diphenylmethylsilyl, a tribenzylsilyl group, and the like. Exemplary trisubstituted silyl protecting groups and their uses are discussed at several places in Greene et al., Protective Groups In Organic Synthesis, 2 nd ed. (John Wiley and Sons, Inc., New York, 1991).
A contemplated peptide synthesis resin is solid phase support also known as a so-called Merrifield""s Peptide Resin that is adapted for synthesis and selective release of hydroxamic acid derivatives as is commercially available from Sigma Chemical Co., St. Louis, Mo. An exemplary peptide synthesis resin so adapted and its use in the synthesis of hydroxamic acid derivatives is discussed in Floyd et al., Tetrahedron Let., 37 (44), pp. 8048-8048 (1996).
A 2-tetrahydropyranyl protecting group is a particularly preferred selectively removable protecting group and is often used when R13 is hydrogen. A contemplated THP-protected hydroxamate compound of Formula C can be prepared by reacting the carboxylic acid precursor compound of Formula C (where R20 is xe2x80x94OH) in water with Oxe2x80x94(tetrahydro-2H-pyran-2-yl)hydroxylamine in the presence of N-methylmorpholine, N-hydroxybenzotriazole hydrate, and a water-soluble carbodiimide (e.g., 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride). The resulting THP-protected hydroxamate corresponds in structure to Formula C3 (below), wherein W, R1, R5, and R6 are as defined previously and more fully hereinafter. The THP protecting group is readily removable in an aqueous acid solution such as an aqueous mixture of p-toluenesulfonic acid or HCl and acetonitrile or methanol.

In view of the above-discussed preferences, compounds corresponding in structure to particular formulas constitute particularly preferred embodiments.
For example, taking into account the before-stated preference that W be a 1,2-phenylene radical, particularly preferred compounds correspond in structure to Formulas VIIC and VIII below, wherein the above definitions for xe2x80x94Axe2x80x94Rxe2x80x94Exe2x80x94Y, xe2x80x94W2, R5, and R6 also apply:

The compounds that correspond in structure to Formulas D, D1, D2, D3, D4 below are also among the particularly preferred compounds contemplated herein:


In each of these formulas, the above definitions for xe2x80x94Axe2x80x94Rxe2x80x94Exe2x80x94Y, R4, R5, R6, and R20 apply and each of A, B, C, and D is independently carbon, nitrogen, sulfur, or oxygen that is present or absent so that the depicted ring has 5- or 6-members. The compound of Example 24, for example, has a structure corresponding to Formula D2. In that compound, R5 and R6 are both methoxy, A is a sulfur atom (i.e., xe2x80x94Sxe2x80x94), R is 1,4-phenylene, E is a bond, and Y is hydrogen. The compound of Example 27 also, for example, corresponds in structure to Formula D2. There, R5 and R6 are again both methoxy, A is an oxygen atom (i.e., xe2x80x94Oxe2x80x94), R is 1,4-phenylene, E is a bond, and Y is a dialkoxy-substituted phenyl.
The compounds that correspond in structure to Formulas E1, E2, E3, E4, and E5 below are also among the particularly preferred compounds contemplated herein:


In each of these formulas, the above definitions for W2, xe2x80x94Axe2x80x94Rxe2x80x94Exe2x80x94Y, R4, R5, R6, and R20 apply.
In some other particularly preferred embodiments, the compound corresponds in structure to Formula F1, F2, F3, F4, F5, F6, F7, F8, F9, F10, F11, F12, F13, or F14:

Here, R1, R4, R6, R20, W2, and xe2x80x94Axe2x80x94Rxe2x80x94Exe2x80x94Y are as defined herein, while R5 is any of the possible substituents listed herein for R5 except hydrogen. Applicants have found that compounds having such an R5 substituent (particularly a polar substituent) tend to exhibit more favorable half-life properties, especially where R20 is xe2x80x94N(H)(OH).
Particularly preferred compounds (and salts thereof) contemplated herein are illustrated herein below (see also the Example section below for a further description of several particularly preferred compounds):

The following Tables 1-58 show several contemplated sulfonyl aryl or heteroaryl hydroxamic acid compounds as structural formulas that illustrate substituent groups. Each group of compounds of Tables 1-58 is illustrated by a generic formula, followed by a series of preferred moieties or groups that constitute various substituents that can be attached at the position shown in the generic structure. One or two bonds (straight lines) are shown with those substituents to indicate the respective positions of attachment in the illustrated compound. This system is well known in the chemical communication arts, and is widely used in scientific papers and presentations. The substituent symbols (e.g., R4, Ar, and X) in these Tables may sometimes be different from those shown in formulas elsewhere in this patent.
Tables 59-73 illustrate specific compounds of the previous tables, as well as other contemplated compounds, using complete molecular formulas.
The compounds of this invention can be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, a salt of the compound may be advantageous due to one or more of the salt""s physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil. In some instances, a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound
Where a salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context), the salt preferably is pharmaceutically acceptable. Pharmaceutically acceptable salts include salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. In general, these salts typically may be prepared by conventional means with a compound of this invention by reacting, for example, the appropriate acid or base with the compound.
Pharmaceutically-acceptable acid addition salts of the compounds of this invention may be prepared from an inorganic or organic acid. Examples of suitable inorganic acids include hydrochloric, hydrobromic acid, hydroionic, nitric, carbonic, sulfuric, and phosphoric acid. Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic, and sulfonic classes of organic acids. Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sulfanilate, cyclohexylaminosulfonate, algenic acid, b-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate.
Pharmaceutically-acceptable base addition salts of the compounds of this invention include, for example, metallic salts and organic salts. Preferred metallic salts include alkali metal (group Ia) salts, alkaline earth metal (group IIa) salts, and other physiological acceptable metal salts. Such salts may be made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. Preferred organic salts can be made from tertiary amines and quaternary amine salts, such as trimethamine, diethylamine, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl (C1-C6) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
Particularly preferred salts of the compounds of this invention include hydrochloric acid (HCl) salts and trifluoroacetate (CF3COOH or TFA) salts.
One embodiment of this invention is directed to a process for preventing or treating a pathological condition associated with MMP activity in a host animal (typically a mammal, such as a human, companion animal, farm animal, laboratory animal, zoo animal, or wild animal) having or disposed to having such a condition. Such a condition may be, for example, tissue destruction, a fibrotic disease, pathological matrix weakening, defective injury repair, a cardiovascular disease, a pulmonary disease, a kidney disease, a liver disease, a bone disease, a central nervous system disease, or cancer. Specific examples of such conditions include osteoarthritis, rheumatoid arthritis, septic arthritis, tumor invasion, tumor metastasis, tumor angiogenesis, a decubitis ulcer, a gastric ulcer, a corneal ulcer, periodontal disease, liver cirrhosis, fibrotic lung disease, otosclerosis, atherosclerosis, multiple sclerosis, dilated cardiomyopathy, epidermolysis bullosa, aortic aneurysm, weak injury repair, an adhesion, scarring, congestive heart failure, coronary thrombosis, emphysema, proteinuria, and Alzheimer""s disease.
The condition may alternatively (or additionally) be associated with TNF-xcex1 activity. Examples of such a condition include inflammation (e.g. rheumatoid arthritis), autoimmune disease, graft rejection, multiple sclerosis, a fibrotic disease, cancer, an infectious disease (e.g., malaria, mycobacterial infection, meningitis, etc.), fever, psoriasis, a cardiovascular disease (e.g., post-ischemic reperfusion injury and congestive heart failure), a pulmonary disease, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage, acute phase responses like those seen with infections and sepsis and during shock (e.g., septic shock, hemodynamic shock, etc.), cachexia, and anorexia.
The condition may alternatively (or additionally) be associated with aggrecanase activity. Examples of such a condition include inflammation diseases (e.g., osteoarthritis, rheumatoid arthritis, joint injury, reactive arthritis, acute pyrophosphate arthritis, and psoriatic arthritis) and cancer.
In this patent, the phrase xe2x80x9cpreventing a conditionxe2x80x9d means reducing the risk of (or delaying) the onset of the condition in a mammal that does not have the condition, but is predisposed to having the condition. In contrast, the phrase xe2x80x9ctreating a conditionxe2x80x9d means ameliorating, suppressing, or eradicating an existing condition. The pathological condition may be (a) the result of pathological MMP and/or aggrecanase activity itself, and/or (b) affected by MMP and/or aggrecanase activity (e.g., diseases associated with TNF-xcex1).
A wide variety of methods may be used alone or in combination to administer the hydroxamates and salt thereof described above. For example, the hydroxamates or salts thereof may be administered orally, parenterally, by inhalation spray, rectally, or topically.
Typically, a compound (or pharmaceutically acceptable salt thereof) described in this patent is administered in an amount effective to inhibit a target MMP(s) and/or aggrecanase. The target MMP is/are typically MMP-2, MMP-9, and/or MMP-13, with MMP-13 often being a particularly preferred target. The preferred total daily dose of the hydroxamate or salt thereof (administered in single or divided doses) is typically from about 0.001 to about 100 mg/kg, more preferably from about 0.001 to about 30 mg/kg, and even more preferably from about 0.01 to about 10 mg/kg (i.e., mg hydroxamate or salt thereof per kg body weight). Dosage unit compositions can contain such amounts or submultiples thereof to make up the daily dose. In many instances, the administration of the compound or salt will be repeated a plurality of times. Multiple doses per day typically may be used to increase the total daily dose, if desired.
Factors affecting the preferred dosage regimen include the type, age, weight, sex, diet, and condition of the patient; the severity of the pathological condition; the route of administration; pharmacological considerations, such as the activity, efficacy, pharmacokinetic, and toxicology profiles of the particular hydroxamate or salt thereof employed; whether a drug delivery system is utilized; and whether the hydroxamate or salt thereof is administered as part of a drug combination. Thus, the dosage regimen actually employed can vary widely, and, therefore, can deviate from the preferred dosage regimen set forth above.
This invention also is directed to pharmaceutical compositions comprising a hydroxamate or salt thereof described above, and to methods for making pharmaceutical compositions (or medicaments) comprising a hydroxamate or salt thereof described above.
The preferred composition depends on the method of administration, and typically comprises one or more conventional pharmaceutically acceptable carriers, adjuvants, and/or vehicles. Formulation of drugs is generally discussed in, for example, Hoover, John E., Remington""s Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.: 1975). See also, Liberman, H. A. See also, Lachman, L., eds., Pharmaceutical Dosage Forms (Marcel Decker, New York, N.Y., 1980). Suitable methods of administration include, for example, oral administration, parenteral administration, rectal administration, topical administration, and administration via inhalation.
Solid dosage forms for oral administration include, for example, capsules, tablets, pills, powders, and granules. In such solid dosage forms, the hydroxamates or salts thereof are ordinarily combined with one or more adjuvants. If administered per os, the hydroxamates or salts thereof can be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled-release formulation, as can be provided in a dispersion of the hydroxamate or salt thereof in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms also can comprise buffering agents, such as sodium citrate, or magnesium or calcium carbonate or bicarbonate. Tablets and pills additionally can be prepared with enteric coatings.
Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also can comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
Parenteral administration includes subcutaneous injections, intravenous injections, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) can be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents. Acceptable vehicles and solvents include, for example, water, 1,3-butanediol, Ringer""s solution, isotonic sodium chloride solution, bland fixed oils (e.g., synthetic mono- or diglycerides), fatty acids (e.g., oleic acid), dimethyl acetamide, surfactants (e.g., ionic and non-ionic detergents), and/or polyethylene glycols.
Formulations for parenteral administration may, for example, be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The hydroxamates or salts thereof can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, com oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
Suppositories for rectal administration can be prepared by, for example, mixing the drug with a suitable nonirritating excipient that is solid at ordinary temperatures, but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, such as cocoa butter; synthetic mono-, di-, or triglycerides; fatty acids; and/or polyethylene glycols.
Topical administration includes the use of transdermal administration, such as transdermal patches or iontophoresis devices.
Inhalation administration includes, for example, nasal sprays.
Other adjuvants and modes of administration known in the pharmaceutical art may also be used.
The following discussion describes exemplary chemical transformations that can be useful for preparing compounds of this invention. The reader also is referred to WIPO Int""l Publ. No. WO 00/69819. The reader is further referred to WIPO Int""l Publ. No. WO 98/38859.
These syntheses, as with all of the reactions discussed herein, can be carried out under a dry, inert atmosphere such as nitrogen (N2) or argon if desired. Selected reactions known to those skilled in the art can be carried out under a dry atmosphere such as dry air, whereas other synthetic steps, like aqueous acid or base ester or amide hydrolyses, can be carried out under laboratory air.
Aryl and heteroaryl aryl compounds of this invention as defined above by W can be prepared in a similar manner as is known to those skilled in the art. It should be understood that the following discussion refers to both heteroaromatics and carbon aromatics even though only one may be specifically mentioned.
In general, the choices of starting material and reaction conditions can vary, as is well known to those skilled in the art. Usually, no single set of conditions is limiting because variations can be applied as required and selected by one skilled in the art. Conditions will also will be selected as desired to suit a specific purpose, such as small scale preparations or large scale preparations. In either case, the use of less safe or less environmentally sound materials or reagents will usually be minimized. Examples of such less desirable materials are diazomethane, diethyl ether, heavy metal salts, dimethyl sulfide, some halogenated solvents, benzene and the like. In addition, many starting materials can be obtained from commercial sources through catalogs or various other arrangements.
An aromatic compound of this invention where y is 1 can be prepared as illustrated (see, e.g., Scheme 1) by converting a carbonyl group bonded to an aromatic (e.g., benzene) ring ortho-substituted with a sulfide. The sulfide can be prepared via a nucleophilic displacement reaction of the ortho fluoride.
The nucleophile can be a thiol or thiolate anion prepared from a aryl thiol discussed below. A preferred thiol is 4-phenoxybenzenethiol converted in situ into its anion (thiolate) using potassium carbonate in iso-propyl alcohol at reflux temperature.
The carbonyl group can be an aldehyde, ketone, or carboxylic acid derivative, i.e., a protected carboxylic acid or hydroxamate. A preferred carbonyl group is an aldehyde and a preferred aldehyde is 2-flourobenzaldehyde (ortho-fluorobenzaldehyde). A ketone can be converted by oxidation into an acid and/or an acid derivative using reagents such as those discussed below for oxidation of a sulfide or other methods well known in the art. It is noted that this oxidation can accomplish the oxidation of a sulfide intermediate into the corresponding sulfone in the same reaction system, i.e., in the same pot, if desired.
The carbonyl group can then be homologated if desired by reaction with an anion to form an addition compound. An example of a homologation reagent is a tri-substituted methane compound such as tetraethyl dimethylammoniummethylenediphosphonate or trimethylorthoformate. Tetraethyl dimethylammoniummethylenediphosphonate is preferred. Hydrolysis of the reaction product can provide a phenylacetic substituted on the aromatic ring with a sulfide of this invention. Acid hydrolysis is preferred. Various suitable acids and bases are discussed below, although HCl is preferred.
The sulfide can then be oxidized to form a sulfone in one or two steps as discussed below. A preferred oxidizing agent is hydrogen peroxide in acetic acid. The carboxylic acid product or intermediate of this invention can then be converted into a protected derivative such as an ester or converted into an activated carboxyl group for reaction with hydroxylamine or protected hydroxylamine. The conversion of an acid into a hydroxamate is discussed below, as is the coupling process and removal of a protecting group if required.
The preferred protected hydroxamic acid derivative is the O-tetrahydropyranyl compound, and the preferred coupling procedure utilizes a diimide (EDC), hydroxybenzotriazol, and DMF solvent for the coupling reaction to form the intermediate hydroxybenzotriazol activated ester. A preferred reagent for removal of the THP protecting group is HCl.
Alkylation of the acid at the carbon alpha to the carbonyl group to form the compounds of this invention can be carried out by first forming an anion using a base. Suitable bases are discussed below, although preferred bases are strong bases that are either hindered and/or non-nucleophilic such as lithium amides, metal hydrides, and lithium alkyls.
Following or during formation of the anion, an alkylating agent (i.e., an electrophile) is added that undergoes a nucleophilic substitution reaction. Nonlimiting examples of such alkylating agents are haloalkanes, dihaloalkanes, haloalkanes also substituted by an activated ester group or activated esters and alkanes substituted with sulfate esters.
Activated ester groups are well known in the art and can include, for example, an activated ester of an alcohol or a halo compound, an ester of a haloalcohol such as a bromo-, iodo- or chloro-derivative of a tosylate, triflate or mesylate activated ester. Compounds wherein, for example, R2 and R3 are taken together as defined above, can be prepared using disubstituted alkylating agent, i.e., alkylating agents with two leaving groups in the same molecule. For example, 1,5-dihalo-diethylether or analogous reagents containing one or more sulfate ester leaving groups replacing one or more halogens can be used to form a pyran ring. A similar sulfur, nitrogen, or protected nitrogen alkylating agent can be used to form a thiapyran or piperidine ring. A thiapyran can be oxidized to form a sulfoxide or a sulfone using methods discussed herein. A leaving group in an electrophilic reagent, as is well known in the art, can be a halogen such as chlorine, bromine or iodine, or an active ester such as a sulfonate ester, e.g., toluenesulfonate (tosylate), triflate, mesylate and the like as discussed above.
The conversion of a cyclic amino acid, heterocycle, or alpha-amino acid defined by R2 and R3 that can include an amino acid (nitrogen heterocycle), which can be protected or unprotected, into a compound of this invention can be accomplished by alkylation or acylation. The carboxylic acid group can be protected with a group such as an alkyl ester such as methyl, ethyl, tert-butyl, and the like or a tetrahydropyranyl ester or an arylalkyl ester such as benzyl or it can remain as a carboxylic acid. A protected amino acid such as an ethyl ester is preferred. The substituent on the heterocycle group is as defined above and can include hydrogen, tert- and iso-butyloxycarbonyl groups. In addition, the amine can be considered as being a protected intermediate as well as being a product of this invention when the N-substituent is not hydrogen.
The nitrogen substituent on the amino acid portion of the compounds of this invention can be varied. In addition, that variation can be accomplished at different stages in the synthetic sequence based on the needs and objectives of the skilled person preparing the compounds of this invention. The nitrogen side chain variations can include replacing the hydrogen substituent with an alkyl, arylalkyl, alkene, or alkyne.
This can be accomplished by methods well known in the art such as alkylation of the amine with an electrophile such as halo- or sulfate ester (activated ester) derivative of the desired side chain. An alkylation reaction is typically carried out in the presence of a base such as those discussed above and in a pure or mixed solvent as discussed above. A preferred base is potassium carbonate and a preferred solvent is DMF.
The alkenes, arylalkenes, arylalkynes, and alkynes so formed can be reduced, for example, by hydrogenation with a metal catalyst and hydrogen, to an alkyl or arylalkyl compound of this invention and an alkyne or arylalkyne can be reduced to an alkene, arylalkene, arylalkane or alkane under catalytic hydrogenation conditions as discussed herein or a deactivated metal catalyst. Catalysts can include, for example, Pd, Pd on Carbon, Pt, PtO2, and the like. Less robust catalysts (deactivated) include such things as Pd on BaCO3 or Pd with quinoline or/and sulfur.
An alternative method for alkylation of the amine nitrogen is reductive alkylation. This process, well known in the art, allows treatment of the secondary amine with an aldehyde or ketone in the presence of a reducing agent such as borane, borane:THF, borane:pyridine, or lithium aluminum hydride. Alternatively, reductive alkylation can be carried out under hydrogenation conditions in the presence of a metal catalyst. Such catalysts, suitable hydrogen pressures, and suitable temperatures are well known in the art. A preferred reductive alkylation catalyst is borane:pyridine complex.
As discussed above, in the case where an intermediate is a carboxylic acid, standard coupling reactions well known in the art can be used to form the compounds of this invention, including protected intermediates. For example, the acid can be converted into an acid chloride, mixed anhydride, or activated ester and reacted with an alcohol, amine, hydroxylamine, or a protected hydroxylamine in the presence of base to form the amide, ester, hydroxamic acid, or protected hydroxamic acid. Suitable bases include N-methyl-morpholine, triethylamine, and the like.
Coupling reactions of this nature are well known in the art, particularly the art related to peptide and amino acid chemistry. Removal of the protecting group can be accomplished, if desired, using standard hydrolysis conditions such as base hydrolysis or exchange or acid exchange or hydrolysis.
The schemes below illustrate conversion of a carboxylic acid protected as an ester or amide into a hydroxamic acid derivative such as a O-arylalkylether or O-cycloalkoxyalkylether group, such as the THP group. Methods of treating an acid or acid derivative with hydroxylamine or a hydroxylamine derivative to form a hydroxamic acid or hydroxamate derivative are discussed above. Hydroxylamine can be used in an exchange reaction by treating a precursor compound where the carboxyl is protected as an ester or amide with one or more equivalents of hydroxylamine hydrochloride or hydroxylamine at room temperature or above to provide a hydroxamic acid directly. The solvent or solvents, usually protic or protic solvent mixtures, include those listed herein.
This exchange process can be further catalyzed by the addition of additional acid. Alternatively, a base (e.g., a salt of an alcohol used as a solvent, such as, for example, sodium methoxide in methanol) can be used to form hydroxylamine from hydroxylamine hydrochloride in situ which can exchange with an ester or amide. As mentioned above, exchange can be carried out with a protected hydroxylamine (e.g., tetrahydropyranyl-hydroxyamine (THPONH2), benzylhydroxylamine (BnONH2), O-(trimethylsilyl)hydroxylamine, and the like), in which case, the compounds formed are tetrahydropyranyl (THP), benzyl (Bn), or TMS hydroxamic acid derivatives. Removal of the protecting groups when desired (e.g., following further transformations in another part of the molecule or following storage) can be accomplished by standard methods well known in the art, such as acid hydrolysis of the THP group as discussed above or reductive removal of the benzyl group with hydrogen and a metal catalyst such as palladium, platinum, palladium on carbon, or nickel.
xcex1-Amino acids or a-hydroxy carboxylic acids or protected carboxylic acids, hydroxamates or hydroxamic acid derivatives or intermediates (precursors) of this invention can be prepared by displacing, for example, a halogen, sulfate ester, or other electrophile, from the alpha carbon of an acid or a derivative as listed. Methods for the halogenation of acids, esters, acid chlorides, and the like are well known in the art and include, for example, the HVZ reaction, treatment with CuCl2, N-bromo- or N-chloro-succinimide, I2, carbon tetraiodide or bromide, and the like. The halogen can be displaced with a nucleophile in an SN2 reaction. Nucleophiles can include hydroxide, ammonia, or amines.
The aryl or heteroaryl carboxylic acids of this invention where Y is 0 and z is 1 can be prepared from heteroaryl or aryl fused lactones. An example of a fused lactone is phthalide. A preferred starting material is phthalide. This compound can be treated with an thiol, thiolate, or metal xe2x80x94SH to undergo an SN2 displacement at the methylene carbon to provide a sulfide or thiol compound of this invention or intermediate to a compound of this invention. A preferred thiol is 4-phenoxybenzenethiol that is used in the presence of potassium carbonate as a preferred base. The sulfide can be oxidized, before or after conversion of the acid to a hydroxamate or hydroxamic acid, to a sulfone of this invention. A preferred oxidizing agent is meta-chloroperbenzoic acid.
A preferred acid activating group is the chloride prepared by reaction of an acid with oxalyl chloride as a preferred reagent. A phthalide or a heteroaryl analog of a phthalide can be treated with a Lewis acid (e.g., zinc chloride or zinc bromide) along with a halogenating reagent (e.g., phosphorus trichloride, thionyl bromide and the like) to form an ortho-(haloalkyl)-aryl acid or ortho-(haloalkyl)heteroaryl acid derivative. Examples include bromomethyl acid bromides and chloromethyl acid chlorides. These carboxylic acids can be derivatized with protecting groups, hydroxamic acids, or hydroxamic acid precursors or hydrolyzed to the acid as required. A preferred hydroxamate-forming reagent is O-(trimethylsilyl)hydroxylamine (TMS-hydroxylamine), and removal of the TMS protecting group is preferably accomplished by acid hydrolysis using HCl.
Displacement (SN2) of the halogen in this example by a thiol in the presence of base or a preformed thiolate can be accomplished as discussed and/or shown and as is well known in the art. Again, oxidation of the sulfide can be carried out before or after derivatization of the carboxylic acid as discussed to prepare the hydroxamic acids of this invention. Removal of the protecting groups can be carried out using acid hydrolysis or reduction as discussed elsewhere.
The alcohols of this invention can be protected or deprotected as required or desired. Protecting groups can include THP ethers, acylated compounds, and various silyl derivatives. These groups, including their protection and removal, are well known in the art.
Examples of bases that can be used include, for example, metal hydroxides, such as sodium, potassium, lithium or magnesium hydroxide; oxides, such as those of sodium, potassium, lithium, calcium or magnesium; metal carbonates, such as those of sodium, potassium, lithium, calcium or magnesium; metal bicarbonates, such as sodium bicarbonate or potassium bicarbonate; primary (Ixc2x0), secondary (IIxc2x0), or tertiary (IIIxc2x0) organic amines, such as alkyl amines, arylalkyl amines, alkylarylalkyl amines, heterocyclic amines, or heteroaryl amines; ammonium hydroxides; and quaternary ammonium hydroxides. As non-limiting examples, such amines can include triethyl amine, trimethyl amine, diisopropyl amine, methyldiisopropyl amine, diazabicyclononane, tribenzyl amine, dimethylbenzyl amine, morpholine, N-methylmorpholine, N,Nxe2x80x2-dimethylpiperazine, N-ethylpiperidine, 1,1,5,5-tetramethylpiperidine, dimethylaminopyridine, pyridine, quinoline, tetramethylethylenediamine, and the like.
Non-limiting examples of ammonium hydroxides, usually made from amines and water, include ammonium hydroxide, triethyl ammonium hydroxide, trimethyl ammonium hydroxide, methyldiiospropyl ammonium hydroxide, tribenzyl ammonium hydroxide, dimethylbenzyl ammonium hydroxide, morpholinium hydroxide, N-methylmorpholinium hydroxide, N,Nxe2x80x2-dimethylpiperazinium hydroxide, N-ethylpiperidinium hydroxide, and the like. As non-limiting examples, quaternary ammonium hydroxides can include tetraethyl ammonium hydroxide, tetramethyl ammonium hydroxide, dimethyldiiospropyl ammonium hydroxide, benzylmethyldiisopropyl ammonium hydroxide, methyldiazabicyclononyl ammonium hydroxide, methyltribenzyl ammonium hydroxide, N,N dimethylmorpholinium hydroxide, N,N,Nxe2x80x2,Nxe2x80x2,-tetramethylpiperazenium hydroxide, and N-ethyl-Nxe2x80x2-hexylpiperidinium hydroxide, and the like. Metal hydrides, amides, or alcoholates such as calcium hydride, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, potassium tert-butoxide, calcium ethoxide, magnesium ethoxide, sodium amide, potassium diisopropyl amide, and the like, can also be suitable reagents. Organometallic deprotonating agents, such as alkyl or aryl lithium reagents (e.g., methyl, phenyl, butyl, iso-butyl, sec-butyl, or tertbutyl lithium), nodium or potassium salts of dimethylsulfoxide, Grignard reagents (e.g., methylmagnesium bromide or methymagnesium chloride), or organocadium reagents (e.g., dimethylcadium and the like) can also serve as bases for causing salt formation or catalyzing the reaction. Quaternary ammonium hydroxides or mixed salts are also useful for aiding phase transfer couplings or serving as phase transfer reagents. The preferred base for use in the alkylation reaction is lithium diisopropyl amide.
Reaction media in general can be comprised of a single solvent, mixed solvents of the same or different classes, or serve as a reagent in a single or mixed solvent system. The solvents can be protic, non-protic, or dipolar aprotic. Non-limiting examples of protic solvents include water, methanol (MeOH), denatured or pure 95% or absolute ethanol, isopropanol, and the like.
Typical non-protic solvents include acetone, tetrahydrofurane (THF), dioxane, diethylether, tert-butylmethyl ether (TBME), aromatics (e.g., xylene, toluene, or benzene), ethyl acetate, methyl acetate, butyl acetate, trichloroethane, methylene chloride, ethylenedichloride (EDC), hexane, heptane, isooctane, cyclohexane, and the like. Dipolar aprotic solvents include dimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile, nitromethane, tetramethylurea, N-methylpyrrolidone, and the like.
Non-limiting examples of reagents that can be used as solvents or as part of a mixed solvent system include organic or inorganic mono- or multi-protic acids or bases such as hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, triethylamine, morpholine, N-methylmorpholine, piperidine, pyrazine, piperazine, pyridine, potassium hydroxide, sodium hydroxide, alcohols or amines for making esters or amides, or thiols for making the products of this invention and the like. Room temperature or less or moderate warming (xe2x88x9210xc2x0 C. to 60xc2x0 C.) are the preferred temperatures of the reaction. If desired, the reaction temperature may be from about xe2x88x9278xc2x0 C. to the reflux point of the reaction solvent or solvents. The preferred solvent for an alkylation reaction is tetrahydrofurane (THF).
Acids are used in many reactions during various synthesis. The Schemes below and this discussion illustrate using acid for removing a THP protecting group to produce a hydroxamic acid, removing a tert-butoxy carbonyl group, hydroxylamine/ester exchange, and the like. Acid hydrolysis of carboxylic acid protecting groups or derivatives is well known in the art. These methods, as is well known in the art, can use acid or acidic catalysts. The acid can be mono-, di-, or tri-protic organic or inorganic acids. Examples of acids include hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, hydrobromic acid, hydrofluoric acid, carbonic acid, phosphorus acid, p-toluene sulfonic acid, trifluoromethane sulfonic acid, trifluoroacetic acid, difluoroacetic acid, benzoic acid, methane sulfonic acid, benzene sulfonic acid, 2,6-dimethylbenzene sulfonic acid, trichloroacetic acid, nitrobenzoic acid, dinitrobenzoic acid, trinitrobenzoic acid, and the like. They can also be Lewis acids such as aluminum chloride, borontrifluoride, antimony pentafluoride, and the like.
Contemplated compounds can include compounds wherein a nitrogen of an amine is acylated to provide, for example, amino acid carbamates. Nonlimiting examples of these carbamates are the carbobenzoxycarbonyl (Z, CBZ, benzyloxycarbonyl), iso-butoxycarbonyl and tert-butoxycarbonyl (BOC, t-BOC) compounds. The materials can be made, as discussed above, at various stages in the synthesis based on the needs and decisions made by a person skilled in the art using methods well know in the art.
Useful synthetic techniques and reagents include those used in protein, peptide, and amino acid synthesis, coupling, and transformation chemistry. The use of the tert-butoxycarbonyl (BOC) and benzyloxycarbonyl (Z), as will as their synthesis and removal, are examples of such protection or synthesis schemes. Transformations of amino acids, amino esters, amino acid hydroxamates, amino acid hydroxamate derivatives, and amino acid amides of this invention or compounds used in this invention is discussed herein or/and shown in the schemes below. This includes, for example, active ester or mixed anhydride couplings wherein preferred bases, if required, are tertiary amines, such as N-methylmorpholine. Reagents for protection of the amine group of the protected amino acids include carbobenzoxy chloride, iso-butylchloroformate, tert-butoxycarbonyl chloride, di-tert-butyl dicarbonate and the like which are reacted with the amine in non-protic or dipolar aprotic solvents such as DMF or THF or mixtures of solvents.
Removal of protecting groups such as carbamates, silyl groups and benzyl, p-methoxybenzyl, or other substituted benzyl groups or diphenylmethyl (benzhydryl) or triphenylmethyl (trityl) can be carried out at different stages in the synthesis of the compounds of this invention as required by methods selected by one skilled in the art. These methods are well known in the art including the amino acid, amino acid coupling, peptide synthesis, and peptide mimetic synthesis art. Removal methods can include catalytic hydrogenation, base hydrolysis, carbonyl addition reactions, acid hydrolysis, and the like. Both the preparation and removal of protecting groups (e.g., carbamates, benzyl groups, and/or substituted arylalkyl groups) are discussed in Green, T., Protecting Groups in Organic Chemistry, 2 nd ed. (John Wiley and Sons, New York, 1991). A preferred method of removal of a BOC group is HCl gas in methylene chloride, which, following normal workup, provides directly an HCl salt of an aminoacid of this invention.
Sulfone compounds, such as those where R1 is nitrobenzene, can be prepared as compounds of this invention by synthesis of a thiol, displacement of an electrophile by the nucleophilic thiol or thiolate, and oxidation of the product thiol ether to the sulfone. For example, displacement of the electrophilic group with a nitro-benzene thiol can yield a compound where R1 is nitrobenzene, whose nitro group can be reduced to provide a useful amino compound wherein R1 is an aniline. It should be noted that nitrobenzenethiol is an example and not to be considered as limiting or required. Oxidation of the thioether product can be carried out as discussed below when desired.
The reduction of nitro groups to amines is well known in the art, with a preferred method being hydrogenation. There is usually a metal catalyst such as Rh, Pd, Pt, Ni, or the like with or without an additional support such as carbon, barium carbonate, and the like. Solvents can be protic or non-protic pure solvents or mixed solvents as required. The reductions can be carried out at atmospheric pressure to a pressure of multiple atmospheres, with atmospheric pressure to about 40 pounds per square inch (psi) being preferred.
The resulting amino group can be alkylated if desired. It can also be acylated with, for example, an aroyl chloride, heteroaryl chloride, or other amine carbonyl forming agent to form an R1 amide of this invention. The amino sulfone or thioether can also be reacted with a carbonic acid ester chloride, a sulfonyl chloride, a carbamoyl chloride, or an isocyanate to produce the corresponding carbamate, sulfonamides, or ureas of this invention. Acylation of amines of this type are well known in the art and the reagents are also well known.
Usually these reactions are carried out in aprotic solvents under an inert or/and dry atmosphere at about 45xc2x0 C. to about xe2x88x9210xc2x0 C. An equivalent of a non-competitive base is usually used with sulfonyl chloride, acid chloride, or carbonyl chloride reagents. Following or before this acylation step, synthesis of the hydroxamic acid products of this invention can proceed as discussed.
Other thiol reagents can also be used in the preparation of compounds of this invention. Examples are fluoroaryl, fluoroheteroaryl, azidoaryl or azidoheteroaryl, or heteroaryl thiol reagents. These thiols can be used a nucleophiles to as discussed above. Oxidation to the corresponding sulfone can then be carried out.
The sulfones, if substituted by a hydrazine or substituted hydrazine, can be oxidized to a hydrazone of this invention. The fluoro-substituted sulfone can be treated with a nucleophile such as ammonia, a primary amine, a quaternary ammonium or metal azide salt, or a hydrazine under pressure if desired, to provide an azido, amino, substituted amino or hydrazino group. Azides can be reduced to an amino group using, for example, hydrogen with a metal catalyst or metal chelate catalyst or by an activated hydride transfer reagent. The amines can be acylated as discussed above.
Methods of preparing useful aminethiol intermediates include protection of an aromatic or heteroaromatic thiol with trityl chloride to form the trityl thiol derivative, treatment of the amine with as reagent such as an aromatic or heteraromatic acid chloride to form the amide, and removal of the trityl group with acid to form the thiol. Acylating agents include benzoyl chloride, and trityl removing reagents include triflouroacetic acid and triisopropylsilane.
The fluorine on the fluorosulfones of this invention can also be displaced with other aryl or heteroaryl nucleophiles to form compounds of this invention. Examples of such nucleophiles include salts of phenols, thiophenols, xe2x80x94OH containing aromatic heterocyclic compounds, or xe2x80x94SH containing heteroaryl compounds. Tautomers of such groups azo, hydrazo, xe2x80x94OH or xe2x80x94SH are specifically included as useful isomers.
A preferred method of preparing intermediates in the synthesis of the substituted sulfones is by oxidation of an appropriate acetophenone, prepared from a fluoroacetophenone, with for example, peroxymonosulfate, to form the corresponding phenol-ether. The phenol-ether is converted into its dimethylthiocarbamoyl derivative using dimethylthiocarbamoyl chloride, rearranged into the dimethylthiocarbamoyl derivative with heat to provide the thiol required for preparation of the thioether intermediate discussed and/or shown in the schemes.
The compounds of this invention, including protected compounds or intermediates, can be oxidized to the sulfones as shown in the schemes and/or discussed above. The selection of the stage of the alternative synthesis to implement this conversion of sulfides into the sulfones or sulfoxides can be carried out by one skilled in the art.
Reagents for this oxidation process may, in a non-limiting example, include peroxymonosulfate (OXONE(copyright)), hydrogen peroxide, meta-chloroperbenzoic acid, perbenzoic acid, peracetic acid, perlactic acid, tert-butyl peroxide, tert-butyl hydroperoxide, tert-butyl hypochlorite, sodium hypochlorite, hypochlorus acid, sodium meta-peroiodate, periodic acid, ozone, and the like. Protic, non-protic, dipolar aprotic solvents, either pure or mixed, can be chosen, for example, methanol/water. The oxidation can be carried out at temperature of from about xe2x88x9278xc2x0 to about 50xc2x0 C., and normally selected from about xe2x88x9210xc2x0C. to about 40xc2x0 C.
Preparation of the sulfones can also be carried out in two steps by oxidizing a sulfide to a sulfoxide, followed by oxidizing the sulfoxide to the sulfone. This can occur in one pot or by isolation of the sulfoxide. This latter oxidation can be carried out in a manner similar to the oxidation directly to the sulfone, except that about one equivalent of oxidizing agent can be used preferably at a lower temperature such as about 0xc2x0 C. Preferred oxidizing agents include peroxymonosulfate and meta-chloroperbenzoic acid.
A sulfonamide of this invention can be prepared in a similar manner using methods and procedures discussed hereinbefore. Aryl, substituted aryl, heteroaryl or substituted heteroaryl dicarboxylic anhydrides, imides (e.g., phthalic anhydrides or imides), their sulfonyl analogs or mixed carboxylic-sulfonic acid amides, imides (e.g., 1,2-benzenethiazole-3(2H)-one 1,1-dioxides) or anhydrides are useful starting material substrates. Reactions utilizing such substrates can be carried out before or after changes in the substitution patterns of the aryl or heteroaryl rings are made.
The sulfonamides can also be prepared from heterocyclic compounds such as saccharine, saccharine analogs, and saccharine homologs. Such compounds and methods are well known in the literature. For example, alkylation of sodium saccharine followed by ring opening or ring opening followed by alkylation permits coupling to form a protected hydroxamic acid derivative such as a THP (tetrahydropyranyl) or TMS (trimethylsilyl) derivative. Hydrolysis of the protecting group provides the hydroxamic acid. The sulfonamide nitrogen can be further alkylated, acylated, or otherwise treated to form various compounds at this stage of prior to coupling and deprotection.
As a non-limiting example, treatment of a mixed sulfonic/carboxylic anhydride (2-sulfobenzoic acid cyclic anhydride) with an alcohol or the salt of an alcohol or a protected hydroxamic acid provides a ring opened carboxylic acid derivative (ester or anhydride, respectively) as a sulfonic acid or salt. The carboxylic acid derivative so prepared is a product of this invention, and can be converted by standard procedures with reagents such as thionyl chloride, phosphorus pentachloride, or the like into a sulfonylhalide.
Reaction of the sulfonylhalide with a primary amine, secondary amine or ammonia with or without added base provides a sulfonamide or sulfonimide of this invention, a sulfonamide that can be alkylated to produce a sulfonamide of this invention or an intermediate to a sulfonamide of this invention. These imides or amides of sulfonamides can be alkylated as desired before or after opening to a benzoic acid substituted sulfonamide or phenylacetic acid substituted sulfonamide.
Compounds prepared as above with protected carboxyl groups are readily converted by exchange, combination exchange/hydrolysis or hydrolysis-coupling processes into the hydroxamic acids of this invention. The exchange/conversion of esters, amides, and protected hydroxylamines (protected hydroxamic acids) into hydroxamic acids is discussed herein. For example, a sulfonamide-ester can be hydrolyzed to a carboxylic acid that is coupled via a benzotriazole active ester with a THP-hydroxylamine reagent and then deprotected. Phenylacetic acid analogs of the above sulfo benzoic acid compounds can also be used in processes similar to those above to prepare the corresponding phenylacetic-derived compounds of this invention.
Aryl or heteroaryl 5- or 6-member ring thiolactones or dithiolactones are also desirable starting materials for the preparation of compounds of this invention. Such thiolactones can be opened to form protected carboxylic acid derivatives such as esters, amides or hydroxylamides before or after changes in the substitution patterns of the aryl or heteroaryl rings are made. Oxidation of the thiol function can be achieved prior to or following substitution changes depending upon the needs and wishes of the skilled chemist. Sulfur compounds can also be oxidized directly to sulfonyl chloride compounds using oxidizing agents whose mechanism involved putative positive chlorine species oxidizing agents and methods are discussed hereinabove. The sulfonic acid derivatives so obtained are then converted into the sulfonamides of this invention as previously discussed.
Changes in substitution patterns on the rings of the compounds of this invention can be carried out by processes well known in the art. Non-limiting examples of such processes include diazonium chemistry, aromatic ring substitution reactions or addition-elimination sequences, metallation reactions, and halogen metal exchange reactions.
A substituted or unsubstituted aryl or heteroaryl sulfonic acid, sulfonic acid derivative, or sulfonamide of this invention can be prepared starting with a halo-sulfonic acid or a sulfonic acid substituted in such a manner that the corresponding anion can be reacted with carbon dioxide, a carbonyl compound, isocyanate, a halogenating reagent, alkylating reagent, acylating reagent, a protected hydroxylamine isocyanate or isothiocyanate derivative to form a compound of this invention or an intermediate to a compound of this invention. An anion can be formed via, for example, direct metallation or metal-halogen exchange. The substituted or unsubstituted aryl or heteroaryl sulfonic acid, sulfonic acid derivative or sulfonamide can be prepared by sulfonation or chlorosulfonation of the substituted or unsubstituted aryl or heteroaryl compound. Metallation reactions as well as halogen-metal exchange reactions to form the salts of the corresponding anions or complexed anions can be carried out by direct treatment with a metal such as lithium, sodium, potassium, palladium, platinum or their complexes, and the like or treatment with a strong base such as tert-butyl lithium, sec-butyl lithium, and the like as discussed above. These intermediates are then quenched with a reagent such as is discussed elsewhere. The resulting carboxylic acids or carboxylic acid derivatives are converted into the sulfonamides of this invention by methods and processes known in the art and discussed herein.
Salts of the compounds or intermediates of this invention are prepared in the normal manner wherein acidic compounds are reacted with bases such as those discussed above to produce metal or nitrogen containing cation salts. Basic compounds, such as amines, can be treated with an acid to form an amine salt. It is noted that some compounds of this invention can be synthesized by biochemical processes, including mammalian metabolic processes. For example, methoxy groups can be converted by the liver in situ into alcohols and/or phenols. Where more than one methoxy group is present, either or both groups can be independently metabolized to hydroxy compounds. Compounds of the present can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or nonracemic mixtures thereof. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes well known in the art, for example by formation of diastereoisomeric salts by treatment with an optically active acid or base.
Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers.
Still another available method involves synthesis of covalent diastereoisomeric molecules, e.g., esters, amides, acetals, ketals, and the like, by reacting compounds of Formula I with an optically active acid in an activated form, a optically active diol or an optically active isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomericaly pure compound. In some cases hydrolysis to the parent optically active drug is not necessary prior to dosing the patient since the compound can behave as a prodrug. The optically active compounds of Formula I can likewise be obtained by utilizing optically active starting materials.
In addition to the optical isomers or potentially optical isomers discussed above, other types of isomers are specifically intended to be included in this discussion and in this invention. Examples include cis isomers, trans isomers, E isomers, Z isomers, syn-isomers, anti-isomers, tautomers and the like. Aryl, heterocyclo or heteroaryl tautomers, heteroatom isomers and ortho, meta or para substitution isomers are also included as isomers. Solvates or solvent addition compounds such as hydrates or alcoholates are also specifically included both as chemicals of this invention and in, for example, formulations or pharmaceutical compositions for drug delivery.
Where a substituent is designated as, or can be, a hydrogen, the exact chemical nature of a substituent which is other than hydrogen at that position, e.g., a hydrocarbyl radical or a halogen, hydroxy, amino, and the like functional group, is not critical so long as it does not adversely affect the overall activity and/or synthesis procedure. For example, two hydroxyl groups, two amino groups, two thiol groups or a mixture of two hydrogen-heteroatom groups on the same carbon are known not to be stable without protection or as a derivative.
The chemical reactions described above are generally disclosed in terms of their broadest application to the preparation of the compounds of this invention. Occasionally, the reactions can not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifications known to those skilled in the art, e.g., by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, and the like, or other reactions disclosed herein or otherwise conventional, will be applicable to the preparation of the corresponding compounds of this invention. In all preparative methods, all starting materials are known or readily preparable from known starting materials.
Other compounds of this invention that are acids can also form salts. Examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases or basic quaternary ammonium salts.
In some cases, the salts can also be used as an aid in the isolation, purification or resolution of the compounds of this invention.
The following schemes further describe examples of suitable preparation methods for the compounds described in this patent.









The term xe2x80x9chydrocarbylxe2x80x9d (alone or in combination) is used herein as a short hand term to include straight and branched chain aliphatic groups, as well as alicyclic groups that contain only carbon and hydrogen. Thus, alkyl, alkenyl, and alkynyl groups are contemplated, while aromatic hydrocarbons (e.g., phenyl and naphthyl groups), which strictly speaking are also hydrocarbyl groups, are referred to herein as aryl groups, as discussed hereinafter. Where a specific aliphatic hydrocarbyl substituent group is intended, that group is recited (e.g., C1-C4 alkyl, methyl, or dodecenyl). Preferred hydrocarbyl groups contain a chain of from 1 to about 12 carbon atoms, and more preferably from 1 to about 10 carbon atoms.
Alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, and the like. Alkenyl groups include, for example, ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, decenyl, and the like. Alkynyl groups include, for example, ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
A particularly preferred hydrocarbyl is alkyl. As a consequence, a generalized, but more preferred substituent, can be recited by replacing the term xe2x80x9chydrocarbylxe2x80x9d with xe2x80x9calkylxe2x80x9d in any of the substituent groups enumerated herein.
Usual chemical suffix nomenclature is followed when using the term xe2x80x9chydrocarbylxe2x80x9d except that the usual practice of removing the terminal xe2x80x9cylxe2x80x9d and adding an appropriate suffix is not always followed because of the possible similarity of a resulting name to one or more substituents. Thus, a hydrocarbyl ether is referred to as xe2x80x9chydrocarbyloxyxe2x80x9d rather than xe2x80x9chydrocarboxyxe2x80x9d as may possibly be more proper when following the usual rules of chemical nomenclature. On the other hand, a hydrocarbyl containing a xe2x80x94C(O)Oxe2x80x94 functionality is referred to as hydrocarboyl inasmuch as there is no ambiguity in using that suffix. As one skilled in the art will understand, a substituent that cannot exist (e.g., C1-alkenyl group) is not intended to be encompassed by the term xe2x80x9chydrocarbylxe2x80x9d.
The term xe2x80x9ccarbonylxe2x80x9d (alone or in combination) means xe2x80x94C(xe2x95x90O)xe2x80x94.
The term xe2x80x9cthiolxe2x80x9d or xe2x80x9csulfhydrylxe2x80x9d (alone or in combination) means xe2x80x94SH.
The term xe2x80x9cthioxe2x80x9d or xe2x80x9cthiaxe2x80x9d (alone or in combination) means a thiaether group, i.e., an ether group wherein the ether oxygen is replaced by a sulfur atom, as in a thiophenoxy group (C6H5xe2x80x94Sxe2x80x94).
The term xe2x80x9caminoxe2x80x9d (alone or in combination) means an amine group or xe2x80x94NH2. The term xe2x80x9cmono-substituted aminoxe2x80x9d (alone or in combination) means an amine group wherein one hydrogen atom is replaced with a substituent, i.e., xe2x80x94N(H)(substituent). The term xe2x80x9cdi-substituted aminexe2x80x9d (alone or in combination) means an amine group wherein both hydrogen atoms are replaced identical or different substituents, i.e., xe2x80x94N(substituent)2. Amino groups, amines, and amides are classes that can be designated as primary (Ixc2x0), secondary (IIxc2x0), or tertiary (IIIxc2x0) or as unsubstituted, mono-substituted, or di-substituted depending on the degree of substitution of the amino nitrogen. The term xe2x80x9cquaternary amine (IVxc2x0)xe2x80x9d means a nitrogen that has 4 substituents and is positively charged and accompanied by a counter ion, i.e., xe2x80x94N+(substituent)4. The term xe2x80x9cN-oxidexe2x80x9d means a nitrogen that has 4 substituents, wherein one of the substituents is oxygen and the charges are internally compensated, xe2x80x94N+(substituent)3-0xe2x88x92.
The term xe2x80x9ccyanoxe2x80x9d (alone or in combination) means xe2x80x94C N (the xe2x80x9cxe2x80x9d symbol means a triple bond).
The term xe2x80x9cazidoxe2x80x9d (alone or in combination) means xe2x80x94Nxe2x95x90Nxe2x95x90Nxe2x80x94 (the xe2x80x9cxe2x95x90xe2x80x9d symbol means a double bond).
The term xe2x80x9chydroxyxe2x80x9d or xe2x80x9cthydroxylxe2x80x9d (alone or in combination) means xe2x80x94OH.
The term xe2x80x9cnitroxe2x80x9d (alone or in combination) means xe2x80x94NO2.
The term xe2x80x9cazoxe2x80x9d (alone or in combination) means xe2x80x94Nxe2x95x90Nxe2x80x94.
The term xe2x80x9chydrazinoxe2x80x9d (alone or in combination) means xe2x80x94N(H)xe2x80x94N(H)xe2x80x94. The hydrogen atoms of the hydrazino group can be independently replaced with substituents, and the nitrogen atoms can form acid addition salts or be quaternized.
The term xe2x80x9csulfonylxe2x80x9d (alone or in combination) means xe2x80x94S(O)2xe2x80x94.
The term xe2x80x9csulfoxidoxe2x80x9d (alone or in combination) means xe2x80x94S(O)xe2x80x94.
The term xe2x80x9csulfonylamidexe2x80x9d (alone or in combination) means xe2x80x94S(O)2xe2x80x94Nxe2x95x90, wherein the remaining 3 bonds (valences) are independently substituted.
The term xe2x80x9csulfinamidoxe2x80x9d (alone or in combination) means xe2x80x94S(O)xe2x80x94Nxe2x95x90, wherein the remaining 3 bonds are independently substituted.
The term xe2x80x9csulfenamidexe2x80x9d (alone or in combination) means xe2x80x94Sxe2x80x94Nxe2x95x90, wherein the remaining 3 bonds are independently substituted.
The term xe2x80x9chydrocarbyloxyxe2x80x9d (alone or in combination) means a hydrocarbyl ether radical, wherein the term xe2x80x9chydrocarbylxe2x80x9d is as defined above. Hydrocarbyl ether radicals include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, n-butoxy, iso-butoxy, sec-butoxy, tertbutoxy, and the like.
The term xe2x80x9ccyclohydrocarbylxe2x80x9d (alone or in combination) means a cyclic structure that contains only carbon and hydrogen. Such a cyclic structure preferably contains from 3 to about 8 carbon atoms, and more preferably from about 3 to about 6 carbon atoms.
The term xe2x80x9ccyclohydrocarbylhydrocarbylxe2x80x9d (alone or in combination) means a hydrocarbyl radical which is substituted by a cyclohydrocarbyl. Cyclohydrocarbylhydrocarbyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexyl, cyclooctynyl, and the like.
The term xe2x80x9carylxe2x80x9d (alone or in combination) means a phenyl or naphthyl radical that optionally is substituted with one or more substituents selected from the group consisting of hydrocarbyl, hydrocarbyloxy, halogen, hydroxy, amino, nitro, and the like. Such radicals include, for example, unsubstituted phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, and the like.
The term xe2x80x9carylhydrocarbylxe2x80x9d (alone or in combination) means a hydrocarbyl radical as defined above wherein one hydrogen atom is replaced by an aryl radical. Arylhydrocarbyls include, for example, benzyl, 2-phenylethyl, and the like.
The term xe2x80x9carylhydrocarbyloxycarbonylxe2x80x9d (alone or in combination) means xe2x80x94C(O)xe2x80x94O-arylhydrocarbyl. An example of an arylhydrocarbyloxycarbonyl radical is benzyloxycarbonyl.
The term xe2x80x9caryloxyxe2x80x9d (alone or in combination) means aryl-Oxe2x80x94.
The term xe2x80x9caromatic ringxe2x80x9d (alone or in combination, such as xe2x80x9csubstituted-aromatic ring sulfonamidexe2x80x9d, xe2x80x9csubstituted-aromatic ring sulfinamidexe2x80x9d, or xe2x80x9csubstituted-aromatic ring sulfenamidexe2x80x9d) means aryl or heteroaryl as defined above.
The terms xe2x80x9chydrocarbyloylxe2x80x9d and xe2x80x9chydrocarbylcarbonylxe2x80x9d (alone or in combination) mean an acyl radical derived from a hydrocarbylcarboxylic acid. Examples include acetyl, propionyl, acryloyl, butyryl, valeryl, 4-methylvaleryl, and the like.
The term xe2x80x9ccyclohydrocarbylcarbonylxe2x80x9d (alone or in combination) means an acyl group derived from a monocyclic or bridged cyclohydrocarbylcarboxylic acid (e.g., cyclopropanecarbonyl, cyclohexenecarbonyl, adamantanecarbonyl, and the like) or a benzofused monocyclic cyclohydrocarbylcarboxylic acid that is optionally substituted by, for example, a hydrocarbyloylamino group (e.g., 1,2,3,4-tetrahydro-2-naphthoyl, 2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl, and the like).
The terms xe2x80x9carylhydrocarbyloylxe2x80x9d or xe2x80x9carylhydrocarbylcarbonylxe2x80x9d (alone or in combination) mean an acyl radical derived from an aryl-substituted hydrocarbylcarboxylic acid. Examples include phenylacetyl, 3-phenylpropenyl (cinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminocinnamoyl, 4-methoxycinnamoyl, and the like.
The terms xe2x80x9caroylxe2x80x9d and xe2x80x9carylcarbonylxe2x80x9d (alone or in combination) mean an acyl radical derived from an aromatic carboxylic acid. Examples include aromatic carboxylic acids, an optionally substituted benzoic or naphthoic acid (e.g., benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl, 2-naphthoyl, 6-carboxy-2-naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2 naphthoyl, 3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like), and the like.
The heterocyclyl (heterocyclo) or heterocyclohydrocarbyl portion of a heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylhydrocarbyloxycarbonyl, heterocyclohydrocarbyl, or the like is a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic heterocycle that preferably contains from 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen, and sulphur. Such a heterocycle optionally is substituted on (a) one or more carbon atoms by a halogen, alkyl, alkoxy, oxo, and the like; (b) a secondary nitrogen atom (i.e., xe2x80x94NHxe2x80x94) by a hydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloyl, aryl, or arylhydrocarbyl; and/or (c) on a tertiary nitrogen atom by oxido that is attached via a carbon atom. The tertiary nitrogen atom with 3 substituents can also form N-oxide, i.e., xe2x95x90N+(O)xe2x88x92. Such heterocyclyl groups include, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, and the like.
The term xe2x80x9cheteroarylxe2x80x9d (alone or in combination) means an aromatic heterocyclic ring substituent that preferably contains from 1 to 4 hetero ring atoms, i.e., atoms other than carbon forming the ring. Those hetero ring atom(s) is (are independently) selected from the group consisting of nitrogen, sulfur, and oxygen. A heteroaryl group can contain a single 5- or 6-member ring or a fused ring system having two 6-member rings or a 5- and a 6-member ring. Heteroaryl groups include, for example, 6-member rings, such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-member rings, such as 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, and isothiazolyl; 6-/5-member fused rings, such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6-/6-member fused rings, such as 1,2-benzopyronyl, 1,4-benzopyronyl, 2,3-benzopyronyl, 2,1-benzopyronyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1,4-benzoxazinyl.
The heteroaryl portion of a heteroaroyl, heteroaryloxycarbonyl, heteroarylhydrocarbyloyl (heteroarylhydrocarbyl carbonyl) group, or the like is an aromatic monocyclic, bicyclic, or tricyclic heterocycle that contains the hetero atoms and is optionally substituted as defined above with respect to the definition of heterocyclyl.
The term xe2x80x9ccyclohydrocarbylhydrocarbyloxycarbonylxe2x80x9d (alone or in combination) means cyclohydrocarbylhydrocarbyl-Oxe2x80x94C(O)xe2x80x94.
The term xe2x80x9caryloxyhydrocarbyloylxe2x80x9d (alone or in combination) means aryl-O-hydrocarbyloyl.
The term xe2x80x9cheterocyclyloxycarbonylxe2x80x9d (alone or in combination) means heterocyclyl-Oxe2x80x94C(O)xe2x80x94.
The term xe2x80x9cheterocyclylhydrocarbyloylxe2x80x9d (alone or in combination) is an acyl radical derived from a heterocyclyl-substituted hydrocarbylcarboxylic acid.
The term xe2x80x9cheterocyclylhydrocarbyloxycarbonylxe2x80x9d means heterocyclyl-substituted hydrocarbyl-Oxe2x80x94C(O)xe2x80x94.
The term xe2x80x9cheteroaryloxycarbonylxe2x80x9d means an acyl radical derived from a carboxylic acid represented by heteroaryl-Oxe2x80x94COOH.
The term xe2x80x9caminocarbonylxe2x80x9d (alone or in combination) means an amino-substituted carbonyl (carbamoyl) derived from an amino-substituted carboxylic acid, wherein the amino can be a primary, secondary, or tertiary amino group containing substituents selected from the group consisting of hydrogen, hydrocarbyl, aryl, aralkyl, cyclohydrocarbyl, cyclohydrocarbylhydrocarbyl, and the like.
The term xe2x80x9caminohydrocarbyloylxe2x80x9d (alone or in combination) means an acyl group derived from an amino-substituted hydrocarbylcarboxylic acid, wherein the amino can be a primary, secondary, or tertiary amino group containing substituents independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cyclohydrocarbyl, cyclohydrocarbylhydrocarbyl, and the like.
The term xe2x80x9chalogenxe2x80x9d (alone or in combination) means a fluorine radical (which may be depicted as xe2x80x94F), chlorine radical (which may be depicted as xe2x80x94Cl), bromine radical (which may be depicted as xe2x80x94Br), or iodine radical (which may be depicted as xe2x80x94I). Typically, a fluorine radical or chlorine radical is preferred, with a fluorine radical being particularly preferred.
The term xe2x80x9chalohydrocarbylxe2x80x9d (alone or in combination) means a hydrocarbyl radical as defined above, wherein one or more hydrogens are replaced with a halogen. Halohydrocarbyl radicals include, for example, chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and the like.
The term xe2x80x9cperfluorohydrocarbylxe2x80x9d (alone or in combination) means a hydrocarbyl group, wherein each hydrogen has been replaced by a fluorine atom. Perfluorohydrocarbyl groups include, for example, trifluoromethyl, perfluorobutyl, perfluoroisopropyl, perfluorododecyl, perfluorodecyl, and the like.
With reference to the use of the words xe2x80x9ccomprisexe2x80x9d or xe2x80x9ccomprisesxe2x80x9d or xe2x80x9ccomprisingxe2x80x9d in this patent (including the claims), Applicants note that unless the context requires otherwise, those words are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and that Applicants intend each of those words to be so interpreted in construing this patent, including the claims below.